Heterocyclic modulators of hif activity for treatment of disease

ABSTRACT

The present invention relates to compounds and methods which may be useful as inhibitors of HIF pathway activity for the treatment or prevention of cancer and other hypoxia-mediated diseases.

This application is a continuation of U.S. application Ser. No.13/974,258, filed Aug. 23, 2013, which claims the benefit of priority ofU.S. provisional application No. 61/743,131 filed Aug. 24, 2012, thedisclosures of which are expressly incorporated by reference as ifwritten herein in their entireties.

Disclosed herein are new heterocyclic compounds, compositions and theirapplication as a pharmaceutical for the treatment of disease. Methods toinhibit HIF pathway activity through the degradation of the HIFα proteinsubunits in a human or animal subject are also provided for thetreatment of diseases mediated by HIF pathway activity.

The heterodimeric HIF transcription factor is composed of a stable HIF1β(aka ARNT) and an oxygen regulatable HIFα subunit (HIF1α or EPAS1 (akaHIF2α)(Semenza, 2012b). Under normal physiological conditions, thecapacity of the cell to degrade the HIFα subunits exceeds the amount ofHIFα protein that is being synthesized. The HIFα subunit is regulated byhydroxylation at two key proline residues (ie. Pro⁴⁰² and Pro⁵⁶⁴ inHIF1α) by a family of proline hydroxylases (PHD1, PHD2 and PHD3), thatutilize α-ketoglutarate and oxygen as substrates to generatehydroxylated HIFα, succinate and CO₂ (Kaelin and Ratcliffe, 2008).Hydroxylation of HIFα makes it a substrate for the VHL ubiquitin ligasecomplex, which promotes HIFα polyubiquitination, thus targeting HIFα forproteosomal degradation. This process is very rapid at normal oxygenlevels, with a <5 minute half-life of HIFα protein, thus enabling rapidregulation of the complex and HIF activity in response to changes inoxygen levels (Maxwell et al., 1999).

Frequently in disease, the HIF pathway is activated by either reducedoxygen levels or genetic alterations that increase the amount ofstabilized HIFα subunit (Semenza, 2012a). Increased HIFα levels occurthrough several mechanisms that include increased in HIFα subunit mRNAexpression, HIFα protein translation, or through a decrease in HIFαprotein degradation. Increased HIF leads to several biological pathwaysbeing activated through HIF mediated transcription of genes that promotestem cell maintenance, metabolic reprogamming, endothelial tomesenchymal transition (EMT), survival, proliferation, migration, pHregulation and angiogenesis.

A substantial body of preclinical experimentation and clinical evidencehas implicated HIF as an important therapeutic target that is essentialfor the maintenance of a subset of tumors and a potential majorcontributor to therapeutic resistance and residual disease (Kaelin,2011; Kaelin and Ratcliffe, 2008; Li et al., 2005; Semenza, 2012a;Semenza, 2012b). In numerous clinical studies, tumor hypoxia has beenreported to correlate with poor prognosis and incomplete response tocurrent therapeutic agents, including various chemotherapies as well asradiotherapy (Harada et al., 2012; Rohwer and Cramer, 2011; Wilson andHay, 2011). This is most likely due to HIF regulation of procancerousmechanisms, including increased proliferation, activation of survivalpathways such as autophagy, enhanced glycolysis as part of a metabolicreprogramming shift away from oxidative phosphorylation, increasedmigration/invasion promoting metastasis, maintenance of pluripotent“stem cell” population and stimulation of angiogenesis through thesynthesis and secretion of pro-angiogenic growth factors.

The loss of any of several tumor suppressors (i.e. VHL, SDH, FH, TSC andothers) and/or dysregulation of several oncogenic pathways (i.e. RAS andPi3K) activate the HIF pathway and its downstream effector pathways, butdo so in the presence of oxygen creating a “pseudohypoxic” state. Thesesubsets of tumors become dependent on the HIF pathway for theircontinued growth. An example of a genetically driven HIF tumorindication is renal cell carcinoma (RCC), in which the tumor suppressorVHL is inactivated by mutation, deletion or promoter hypermethylation in70% of tumors (Kim and Kaelin, 2004). VHL inactivation results in HIFαstabilization that is independent of oxygen concentration. In anotherexample, tumors where either fumarate hydratase (FH) or a subunit in thesuccinate dehydrogenase (SDH) complex is inactivated, HIFα accumulationoccurs due to inhibition of PHDs by succinate and fumarate (Bardella etal., 2011; Gill, 2012; Isaacs et al., 2005; Pollard et al., 2005). Thelack of HIFα hydroxylation prevents VHL mediated degradation.

In other tumors, the Pi3K pathway is frequently mutated (ie., PTEN loss,AKT, PIK3CA, TSC1/2, LKB1 and others) ultimately leading to an increasein the activity of mammalian target of rapaycin (mTOR), which results inan increase in HIFα protein translation to the point where it overwhelmsthe degradation pathway. Therefore, in tumors with active Pi3K pathway,HIF pathway activity is frequently increased (Wouters and Koritzinsky,2008). Taken together, in tumors where the HIF pathway is driven byspecific genetic changes, therapeutic interventions that inactivate theHIF pathway in genetically driven HIF dependent tumors may providesubstantial therapeutic benefit as monotherapy or as part of acombination therapy.

In addition to the activitation of HIF through genetic alterations, HIFis also activated in hypoxia that results from the tumor outgrowing thevasculature as well as a result of therapeutic intervention. HIFmediated survival of cells in hypoxia is a major contributor toresistance to therapies, lack of durable response and the foundation ofresidual disease. When tumor cells become hypoxic, several HIF dependentmechanisms prolong the survival of the cells in the harsh nutrient andoxygen deprived environment. These include genomic instability topromote adaptation (Klein and Glazer, 2010; Koi and Boland, 2011),metabolic reprogramming, induction of autophagy to recycle energy(Mazure and Pouyssegur, 2010), secretion of pro-angiogenic factors topromote neovascularization and cessation of pro-growth pathways. Severehypoxia mediates innate resistance to radiotherapy and chemotherapy,which require oxygen and proliferation, respectively, as part of theirmechanisms of action. Alternatively, resistance can be adaptive as inthe case of anti-angiogenic therapies, such as anti-VEGF therapies, thatcreate hypoxic niches due to the destruction of the vasculature, whichcreates more intratumoral hypoxia thus activating HIF and promoting itsmilieu of procancerous pathways. Multiple reports in a mouse models ofcancer show that treatment with an anti-VEGF therapy promotedmetastasis, most likely through HIF mediated activation of tumor cellmigration/invasion (Ebos et al., 2009; Paez-Ribes et al., 2009). Hypoxiahas also been proposed to promote genomic alteration by increasing DNAdamage, including impairment of mismatch repair, nucleotide excisionrepair, double strand break repair and homologous recombination repair.The introduction of point mutations, frameshifts, insertions, deletions,amplifications and translocations give rise to tumor heterogeneity andevolution that provide the genetic alterations that enable adaptiveresistance of tumors.

In most tumor types, inhibition of the HIF pathway activity willsenstitize tumors to standard of care therapies such as anti-angiogenictherapies, radiotherapies, chemotherapies and targeted therapies byeither improving the perfusion of drug and oxygen throughout the tumorvia normalization of vascular function (Carmeliet and Jain, 2011;Chauhan et al., 2012) and by directly targeting the resistent HIFactivated tumor cells to inhibit HIF mediated survival pathways.

In addition to cancer, inactivation of HIF pathway activate would bebeneficial for conditions where activation of HIF promotes the diseasestate through aberrant survival or through promotion ofneovascularization. These include traumatic shock, pulmonary arterialhypertension, obstructive sleep apnea, cardiovascular diseases such ascardiac arrhythmia and heart failure, diseases that involveneoangiogenesis such as ocular macular degeneration and rheumatoidarthritis, sepsis and inflammation and diseases of the lung and kidneywhere fibrosis occurs due HIF mediated EMT (Arjamaa et al., 2009;Semenza, 2012a; Westra et al., 2010).

To date, numerous small molecules have been reported that downregulatethe HIF pathway via several direct and indirect mechanisms which targetvarious HIF intervention points (Jones and Harris, 2012; Poon et al.,2009; Semenza, 2012b). These include reducing HIFα mRNA, reducing HIFαprotein translation, reducing reactive oxygen species (ROS), increasingHIFα degradation, disrupting HIFα/HIF1β dimerization or the HIFαinteraction with p300, a co-factor for HIF translation. Genetic andpharmacological inhibition of the HIF pathway utilizing RNAi, geneticablation or via small molecule inhibitors have been reported to reducethe growth of tumors in preclinical models clearly establishing that theHIF pathway performs a critical function in tumor growth and maintenance(Onnis et al., 2009). Promoting HIFα degradation as part of atherapeutic intervention regime would be highly beneficial to patients.Herein we describe a series of selective small molecule inhibitors ofHIF pathway activity that promote VHL and PHD mediated degradation ofHIF.

Novel compounds and pharmaceutical compositions, certain of which havebeen found to inhibit HIF pathway activity have been discovered,together with methods of synthesizing and using the compounds includingmethods for the treatment of HIF pathway-mediated diseases in a patientby administering the compounds.

In certain embodiments of the present invention, compounds havestructural Formula I:

(R₁)_(n)-A-Y₁—B-D-E-(R₃)_(p)  (I)

or a salt thereof, wherein:

n is 0, 1, or 2;

p is 0, 1, or 2;

q is 0, 1, 2, 3, or 4;

u is 0, 1, or 2;

A is selected from the group consisting of aryl and heteroaryl;

B is selected from the group consisting of

D is selected from the group consisting of alkyl, heteroalkyl, alkoxy,alkylthio, carbonyl, alkylcarbonyl, carboxyl, oxy, thio, sulfinyl,sulfonyl, sulfonamido, amino, amido, alkylamino, and heteroaryl, any ofwhich can be optionally substituted with one or more substituentsselected from the group consisting of hydrogen, deuterium, halogen,alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, and oxo, any of which may be optionallysubstituted;

E is selected from the group consisting of aryl and heteroaryl;

G is selected from the group consisting of saturated 3- to 7-memberedcycloalkyl and saturated 3- to 7-membered heterocycloalkyl;

R₁ is selected from the group consisting of —Y₂-alkyl-N(R₄)R₅, hydrogen,deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, aminoalkyl, acyl, carboxylalkyl, carbonyl,carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo,alkylthio, thiolalkyl, mercaptyl, thiol, sulfonate, sulfonamido,alkylsulfonyl, amino, amido, alkylamino, dialkylamino, carbamate, nitro,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy,heterocycloalkyloxy, heteroaryloxy,

cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl,heteroarylcarbonyl, cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl,heterocycloalkylcarbonylalkyl, and heteroarylalkyl, any of which can beoptionally substituted with one or more substituents selected from thegroup consisting of hydrogen, deuterium, halogen, alkyl, alkenyl,alkynyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, amidoalkyl,acyl, carbonyl, carboxyl, carboxylalkyl, alkylcarbonyl,heteroalkylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl,alkylaminoalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkoxyalkyl,carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo,alkylthio, thiol, acylthio, sulfonamido, alkylsulfonyl, amino, amido,carbamate, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl,nitro, trisubstituted silyl, trisubstituted siloxy, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, alkylheterocycloalkyl, any of which may beoptionally substituted;

R₃ is selected from the group consisting of hydrogen, deuterium,halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, acyl, carbonyl, carboxyl, cyano, cyanoalkyl,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, hydroxyalkoxy,oxo, alkylthio, mercaptyl, thiol, haloalkylthio, perhaloalkylthio,cyanoalkylthio, haloalkylsulfonyl, alkylsulfonyl, alkoxyalkylsulfonyl,cyanoalkylsulfonyl, sulfonate, sulfonamido, amino, amido, alkylamino,dialkylamino, carbamate, nitro, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy,cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, and heteroarylalkyl,trisubstituted silyl, —SF₅, —(C(R₃₁)(R₃₂))_(q)—O-alkyl,—(C(R₃₁)(R₃₂))_(q)—O-cycloalkyl, —S(O)_(u)-alkyl, —S(O)_(u)-cycloalkyl,cycloalkylthio, —CF₃, —OCF₃, —(C(R₃₁)(R₃₂))_(q)—OCF₃, saturatedheterocycloalkyloxy, —(C(R₃₁)(R₃₂))_(q)—O-saturated heterocycloalkyl,—(C(R₃₁)(R₃₂))_(q)— saturated heterocycloalkyl, saturatedheterocycloalkylthio, —S(O)_(u)-saturated heterocycloalkyl,—(C(R₃₁)(R₃₂))_(q)—OCF₃,

any of which may be optionally substituted;

R₄ and R₅ are independently selected from the group consisting ofhydrogen, deuterium, alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl, alkoxy, haloalkoxy,perhaloalkoxy, alkylsulfonyl, sulfonamido, amido, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl,heterocycloalkylalkyl, and heteroarylalkyl, or R₄ and R₅, takentogether, form a heterocyloalkyl or heteroaryl, any of which can beoptionally substituted with one or more substituents selected from thegroup consisting of hydrogen, deuterium, halogen, alkyl, alkenyl,alkynyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl,carbonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,oxo, alkylthio, mercaptyl, thiol, sulfonate, sulfonamido, amino, amido,alkylamino, dialkylamino, carbamate, nitro, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy,heterocycloalkyloxy, heteroaryloxy, cycloalkylalkyl, arylalkyl,heterocycloalkylalkyl, and heteroarylalkyl, any of which may beoptionally substituted;

each R₂₃ is independently selected from the group consisting ofhydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, aminoalkyl, acyl, carbonyl, carboxyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio, amino,alkylamino, dialkylamino, nitro, cycloalkyl, aryl, and heteroaryl, anyof which may be optionally substituted;

R₃₁, R₃₂, R₃₃, R₃₄, and R₃₆ are independently selected from the groupconsisting of hydrogen, deuterium, alkyl, and perfluoroalkyl, any ofwhich can be optionally substituted;

R₃₅ is selected from the group consisting of hydrogen, deuterium, alkyl,perfluoroalkyl, cycloalkyl, and saturated heterocycloalkyl, any of whichcan be optionally substituted;

R₃₇ and R₃₈ are independently selected from the group consisting ofalkyl and perfluoroalkyl, or R₃₇ and R₃₈, taken together, form aheterocyloalkyl, any of which can be optionally substituted;

Y₁ is selected from the group consisting of alkyl, alkenyl, alkynyl,heteroalkyl, alkoxy, alkylthio, carbonyl, alkylcarbonyl, carboxyl, oxy,thio, sulfinyl, sulfonyl, sulfonamido, amino, amido, alkylamino, andcarbamate, any of which can be optionally substituted with one or moresubstituents selected from the group consisting of hydrogen, deuterium,halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl,aminoalkyl, acyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy,haloalkoxy, perhaloalkoxy, oxo, alkylthio, amino, alkylamino,dialkylamino, and cycloalkyl, any of which may be optionallysubstituted; and

Y₂ is selected from the group consisting of a bond, carbonyl,alkylcarbonyl, carboxyl, oxy, thio, sulfinyl, sulfonyl, sulfonamido,amino, amido, alkylamino, and carbamate, any of which can be optionallysubstituted with one or more substituents selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, carbonyl,carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo,alkylthio, mercaptyl, thiol, sulfonate, sulfonamido, amino, amido,alkylamino, dialkylamino, carbamate, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy,cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, and heteroarylalkyl,any of which may be optionally substituted.

Certain compounds disclosed herein may possess useful HIF pathwayinhibiting activity, and may be used in the treatment or prophylaxis ofa disease or condition in which the HIF pathway plays an active role.Thus, in broad aspect, certain embodiments also provide pharmaceuticalcompositions comprising one or more compounds disclosed herein togetherwith a pharmaceutically acceptable carrier, as well as methods of makingand using the compounds and compositions. Certain embodiments providemethods for inhibiting the HIF pathway. Other embodiments providemethods for treating a HIF pathway-mediated disorder in a patient inneed of such treatment, comprising administering to said patient atherapeutically effective amount of a compound or composition accordingto the present invention. Also provided is the use of certain compoundsdisclosed herein for use in the manufacture of a medicament for thetreatment of a disease or condition ameliorated by the inhibition of theHIF pathway.

In certain embodiments,

if A is phenyl, B is not

wherein Q₂ and Q₃ are freely substituted;

if A is phenyl or pyridyl, Y₁ is CH₂, B is

and Q₁ is methyl, ethyl, or trifluoromethyl, then D is not

and

wherein * represents the point of attachment to Y₁ and ** represents thepoint of attachment to D, and # represents the point of attachment to Band ## represents the point of attachment to E.

In further embodiments,

A is selected from the group consisting of aryl and mono- or bicyclicheteroaryl;

B is selected from the group consisting of

D is selected from the group consisting of amido, 5-membered heteroaryl,and 6-membered heteroaryl, any of which can be optionally substitutedwith one or more substituents selected from the group consisting ofhydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, acyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, and oxo,any of which may be optionally substituted;

E is selected from the group consisting of phenyl, 5-memberedheteroaryl, 6-membered heteroaryl, and 9-membered bicyclic heteroaryl;

R₄ and R₅ are independently selected from the group consisting ofhydrogen, deuterium, alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl, alkoxy, haloalkoxy,perhaloalkoxy, alkylsulfonyl, sulfonamido, amido, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl,heterocycloalkylalkyl, and heteroarylalkyl, or R₄ and R₅, takentogether, form a heterocyloalkyl or heteroaryl, any of which can beoptionally substituted with one or more substituents selected from thegroup consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl,cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio,mercaptyl, thiol, sulfonamido, amino, amido, alkylamino, dialkylamino,carbamate, and cycloalkyl, any of which may be optionally substituted;

R₂₃ is selected from the group consisting of hydrogen, deuterium,halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl,cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, amino,alkylamino, dialkylamino, cycloalkyl, aryl, and heteroaryl;

Y₁ is alkyl, which can be optionally substituted with one or moresubstituents selected from the group consisting of hydrogen, deuterium,alkyl, cycloalkyl, and halogen; and

Y₂ is selected from the group consisting of a bond, carbonyl,alkylcarbonyl, carboxyl, oxy, thio, sulfinyl, sulfonyl, sulfonamido,amino, amido, alkylamino, and carbamate, any of which can be optionallysubstituted with one or more substituents selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl,cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio,mercaptyl, thiol, sulfonamido, amino, amido, alkylamino, dialkylamino,carbamate, and cycloalkyl, any of which may be optionally substituted.

In further embodiments, B is

In further embodiments, D is selected from the group consisting of—C(═O)NR₁₁—, 5-membered heteroaryl, and 6-membered heteroaryl;

E is selected from the group consisting of phenyl, pyrimidine,1,3-benzodioxol, indole, and 1-benzofuran;

R₁ is selected from the group consisting of —Y₂-alkyl-N(R₄)R₅, hydrogen,deuterium, halogen, alkyl, alkenyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, aminoalkyl, acyl, carboxylalkyl, carbonyl,carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo,alkylthio, thiolalkyl, sulfonamido, alkylsulfonyl, amino, amido,alkylamino, dialkylamino, nitro, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy,

cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl, andheterocycloalkylcarbonylalkyl, any of which can be optionallysubstituted with one or more substituents selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl,amidoalkyl, acyl, carboxylalkyl, alkylcarbonyl, heteroalkylcarbonyl,hydroxyalkylcarbonyl, aminoalkylcarbonyl, alkylaminoalkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, alkoxyalkyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, oxo, thiol, acylthio, sulfonamido, alkylsulfonyl, amino,amido, carbamate, alkylamino, dialkylamino, alkylaminoalkyl,dialkylaminoalkyl, trisubstituted silyl, trisubstituted siloxy,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, alkylheterocycloalkyl,any of which may be optionally substituted;

R₃ is selected from the group consisting of hydrogen, deuterium,halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, dialkylamino, acyl, carbonyl, carboxyl, cyano,cyanoalkyl, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy,hydroxyalkoxy, oxo, alkylthio, haloalkylthio, perhaloalkylthio,cyanoalkylthio, alkylsulfonyl, alkoxyalkylsulfonyl, cyanoalkylsulfonyl,haloalkylsulfonyl, sulfonamido, alkylsulfonamido, amino, alkylamino,dialkylamino, amido, cycloalkyl, aryl, heterocycloalkyl, heteroarylperhaloalkylcycloalkyl, hydroxyheterocycloalkyl, hydroxycycloalkyl,heterocycloalkylcarbonyl, and heterocycloalkylalkyl, any of which can beoptionally substituted;

R₁₁ is selected from the group consisting of hydrogen, deuterium, alkyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl, any of which may be optionallysubstituted;

Y₁ is —CH₂—; and

Y₂ is selected from the group consisting of a bond, carbonyl, amino, andalkylamino.

In further embodiments,

A is selected from the group consisting of phenyl, 5-memberedheteroaryl, and 6-membered heteroaryl;

E is phenyl;

R₁ is selected from the group consisting of —Y₂-alkyl-N(R₄)R₅, hydrogen,deuterium, halogen, alkyl, alkenyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, acyl, carboxylalkyl, carboxyl, carbonyl,cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, thiolalkyl,sulfonyl, sulfonamido, alkylsulfonyl, amino, amido, alkylamino,dialkylamino, nitro, heterocycloalkyl, heterocycloalkyloxy,

heterocycloalkylcarbonylalkyl, and heterocycloalkylcarbonyl, any ofwhich can be optionally substituted with one or more substituentsselected from the group consisting of hydrogen, deuterium, halogen,alkyl, alkenyl, amidoalkyl, acyl, carboxylalkyl, hydroxyalkylcarbonyl,alkynylcarbonyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, carboxyl,cyano, hydroxy, alkoxy, oxo, sulfonamido, alkylsulfonyl, amino, amido,carbamate, dialkylamino, dialkylaminoalkyl, trisubstituted siloxy,cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, any of which may beoptionally substituted;

R₁₁ is selected from the group consisting of hydrogen, deuterium, alkyl,and cycloalkyl, any of which may be optionally substituted; and

each R₂₃ is independently selected from the group consisting ofhydrogen, deuterium, hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano,saturated 3- to 6-membered cycloalkyl, 4- to 6-memberedheterocycloalkyl, and 5- to 6-membered heteroaryl.

In further embodiments of the present invention, n is 1; p is 1; and R₂₃is selected from the group consisting of alkyl, haloalkyl, perhaloalkyl,hydroxy, and cyclopropyl.

In certain embodiments, disclosed herein are compounds having structuralFormula II

or a salt thereof, wherein:

X₂, X₄, and X₅ are independently selected from the group consisting ofCR₂₁, N, O, and S, and wherein X₂, X₄, and X₅, taken together, form a5-membered heteroaryl;

Z₁ and Z₂ are independently selected from the group consisting of N,NR₁, C═O, and CR₁;

Z₃ is selected from the group consisting of N, NR₁₂, C═O, and CR₁₂;

R₁ is selected from the group consisting of —Y₂-alkyl-N(R₄)R₅, hydrogen,deuterium, halogen, alkyl, alkenyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, aminoalkyl, acyl, carboxylalkyl, carbonyl,carboxyl, carbonyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,oxo, alkylthio, thiolalkyl, sulfonyl, sulfonamido, alkylsulfonyl, amino,amido, alkylamino, dialkylamino, nitro, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy,heterocycloalkyloxy, heteroaryloxy,

cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl, andheterocycloalkylcarbonylalkyl, any of which can be optionallysubstituted with one or more substituents selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl,amidoalkyl, acyl, carboxylalkyl, alkylcarbonyl, heteroalkylcarbonyl,hydroxyalkylcarbonyl, aminoalkylcarbonyl, alkylaminoalkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, alkoxyalkyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, oxo, thiol, acylthio, sulfonamido, alkylsulfonyl, amino,amido, carbamate, alkylamino, dialkylamino, alkylaminoalkyl,dialkylaminoalkyl, trisubstituted silyl, trisubstituted siloxy,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, alkylheterocycloalkyl,any of which may be optionally substituted;

R₁₂, R₁₃, and R₁₄ are independently selected from the group consistingof hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, amino, andsaturated 3- to 7-membered cycloalkyl, any of which may be optionallysubstituted;

R₁₆, R₁₉, and R₂₀ are independently selected from the group consistingof hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, amino, andcycloalkyl, any of which may be optionally substituted;

R₁₇ and R₁₈ are independently selected from the group consisting ofhydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, dialkylamino, acyl,carbonyl, carboxyl, cyano, cyanoalkyl, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, alkoxyalkoxy, hydroxyalkoxy, oxo, alkylthio,haloalkylthio, perhaloalkylthio, cyanoalkylthio, alkylsulfonyl,alkoxyalkylsulfonyl, cyanoalkylsulfonyl, haloalkylsulfonyl, sulfonamido,alkylsulfonamido, amino, alkylamino, dialkylamino, amido, cycloalkyl,aryl, heterocycloalkyl, heteroaryl perhaloalkylcycloalkyl,hydroxyheterocycloalkyl, hydroxycycloalkyl, heterocycloalkylcarbonyl,and heterocycloalkylalkyl, any of which can be optionally substituted;

R₂₁ is selected from the group consisting of null, hydrogen, deuterium,halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl,cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, amino,alkylamino, and dialkylamino; and

R₂₃ is selected from the group consisting of hydrogen, deuterium,hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, saturated 3- to6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to6-membered heteroaryl.

In further embodiments,

two of X₂, X₄, and X₅ are N; and one of X₂, X₄, and X₅ is O; or

one of X₂, X₄, and X₅ is N; one of X₂, X₄, and X₅ is O; and one of X₂,X₄, and X₅ is CH; and

R₂₃ is selected from the group consisting of hydrogen, deuterium,hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, and saturated 3- to6-membered cycloalkyl.

In further embodiments,

at least one of Z₁ or Z₂ is CR₁;

R₁ is selected from the group consisting of —Y₂-alkyl-N(R₄)R₅, hydrogen,deuterium, halogen, alkyl, alkenyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, acyl, carboxylalkyl, carboxyl, carbonyl,cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, thiolalkyl,sulfonyl, sulfonamido, alkylsulfonyl, amino, amido, alkylamino,dialkylamino, nitro, heterocycloalkyl, heterocycloalkyloxy,

heterocycloalkylcarbonylalkyl, and heterocycloalkylcarbonyl, any ofwhich can be optionally substituted with one or more substituentsselected from the group consisting of hydrogen, deuterium, halogen,alkyl, alkenyl, amidoalkyl, acyl, carboxylalkyl, hydroxyalkylcarbonyl,alkynylcarbonyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, carboxyl,cyano, hydroxy, alkoxy, oxo, sulfonamido, alkylsulfonyl, amino, amido,carbamate, dialkylamino, dialkylaminoalkyl, trisubstituted siloxy,cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, any of which may beoptionally substituted;

R₁₂, R₁₃, and R₁₄ are hydrogen;

R₁₆, R₁₇, R₁₉, and R₂₀ are hydrogen;

R₂₁ is selected from the group consisting of null, hydrogen, deuterium,halogen, and alkyl; and

R₂₃ is selected from the group consisting of hydrogen, deuterium,hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, and saturated 3- to6-membered cycloalkyl.

In further embodiments,

R₁ is selected from the group consisting of hydrogen, deuterium,fluorine, bromine, cyano, methyl, isopropyl,

ethylene,

trifluoromethyl, bromomethyl, hydroxymethyl, difluoromethoxy, methoxy,ethoxy, isopropoxy, hydroxy, nitro, acetyl, carboxyl, —CO₂CH₃,

—SO₂CH₃, —SO₂CH₂CH₃, SO₂CH₂CH₂CH₃, —SO₂NH₂,

amino, methylamino, dimethylamino,

R₁₈ is selected from the group consisting of hydrogen, deuterium,halogen, methyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, acetyl,hydroxymethyl, methoxymethyl, methoxy, isopropoxy, methylamino,dimethylamino, methylthio, cyanomethyl, cyanomethylthio, cyano, —SO₂CH₃,—SO₂CH(CH₃)₂, —SO₂CH₂CH(CH₃)₂, —SO₂NHCH₂CH₂CH₃, —SO₂CHF₂, —SO₂CF₃,

trifluoromethyl, trifluoromethylthio, difluoromethoxy, andtrifluoromethoxy;

R₂₂ is selected from the group consisting of hydrogen, deuterium,methyl, acetyl,

and

R₂₃ is selected from the group consisting of hydrogen, deuterium,methyl, ethyl, 3-pyridyl, and cyclopropyl.

In further embodiments,

R₁ is selected from the group consisting of hydrogen, halogen, cyano,methyl, isopropyl,

ethylene, trifluoromethyl, difluoromethoxy, methoxy, ethoxy, isopropoxy,hydroxy, carboxyl, —CO₂CH₃, —SO₂CH₃, —SO₂NH₂,

amino, methylamino, dimethylamino,

and

R₂₃ is methyl.

In further embodiments, two of X₂, X₄, and X₅ are N; and one of X₂, X₄,and X₅ is O.

In further embodiments, one of X₂, X₄, and X₅ is N; one of X₂, X₄, andX₅ is O; and one of X₂, X₄, and X₅ is CH.

In certain embodiments, disclosed herein are compounds having structuralFormula III:

or a salt thereof, wherein:

X₂ and X₄ are N and X₅ is O; X₄ and X₅ are N and X₂ is O; X₂ and X₅ areN and X₄ is O; X₂ is CH, X₄ is N, and X₅ is O; or X₂ is CH, X₄ is O, andX₅ is N;

Z₂ is selected from the group consisting of N and CR₁₄;

R₁ is selected from the group consisting of heterocycloalkyl,alkoxyalkoxy, alkylsulfonylalkoxy, heterocycloalkyloxy,heterocycloalkylcarbonyl, alkoxyalkylamido, heterocycloalkylsulfonyl,alkoxyalkylsulfonamido, wherein said heterocycloalkyl,heterocycloalkyloxy, heterocycloalkylcarbonyl, andheterocycloalkylsulfonyl can be optionally substituted with one or moresubstituents selected from the group consisting hydrogen, alkyl, andoxo;

R₁₄, R₃₉, and R₄₀ are independently selected from the group consistingof hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, amino, andsaturated 3- to 7-membered cycloalkyl, any of which may be optionallysubstituted; and

R₁₈ is selected from the group consisting of alkyl, haloalkyl,perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio,haloalkylthio, and perhaloalkylthio.

In further embodiments, R₁ is selected from the group consisting of

In further embodiments, R₁₈ is selected from the group consisting ofisopropyl, tert-butyl, —CF₃, —OCF₃, —OCHF₂, and —SCF₃.

In further embodiments, R₁ is selected from the group consisting of

R₁₃, R₁₄, R₁₆, R₁₇, and R₁₉ are hydrogen; and

R₁₈ is selected from the group consisting of isopropyl, tert-butyl,—CF₃, —OCF₃, —OCHF₂, and —SCF₃.

In certain embodiments, disclosed herein are compounds having structuralFormula IV:

or a salt thereof, wherein:

Z₁ and Z₂ are independently selected from the group consisting of N,NR₁, C═O, and CR₁;

Z₃ is selected from the group consisting of N, NR₁₂, C═O, and CR₁₂; R₁is selected from the group consisting of —Y₂-alkyl-N(R₄)R₅, hydrogen,deuterium, halogen, alkyl, alkenyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, aminoalkyl, acyl, carboxylalkyl, carbonyl,carboxyl, carbonyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,oxo, alkylthio, thiolalkyl, sulfonyl, sulfonamido, alkylsulfonyl, amino,amido, alkylamino, dialkylamino, nitro, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy,heterocycloalkyloxy, heteroaryloxy,

cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl, andheterocycloalkylcarbonylalkyl, any of which can be optionallysubstituted with one or more substituents selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl,amidoalkyl, acyl, carboxylalkyl, alkylcarbonyl, heteroalkylcarbonyl,hydroxyalkylcarbonyl, aminoalkylcarbonyl, alkylaminoalkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, alkoxyalkyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, oxo, thiol, acylthio, sulfonamido, alkylsulfonyl, amino,amido, carbamate, alkylamino, dialkylamino, alkylaminoalkyl,dialkylaminoalkyl, trisubstituted silyl, trisubstituted siloxy,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, alkylheterocycloalkyl,any of which may be optionally substituted;

R₁₁ is selected from the group consisting of hydrogen, deuterium, alkyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl;

R₁₂, R₁₃, and R₁₄ are independently selected from the group consistingof hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, amino, andsaturated 3- to 7-membered cycloalkyl, any of which may be optionallysubstituted;

R₁₆, R₁₉, and R₂₀ are independently selected from the group consistingof hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, amino, andcycloalkyl, any of which may be optionally substituted;

R₁₇ and R₁₈ are independently selected from the group consisting ofhydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, dialkylamino, acyl,carbonyl, carboxyl, cyano, cyanoalkyl, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, alkoxyalkoxy, hydroxyalkoxy, oxo, alkylthio,haloalkylthio, perhaloalkylthio, cyanoalkylthio, alkylsulfonyl,alkoxyalkylsulfonyl, cyanoalkylsulfonyl, haloalkylsulfonyl, sulfonamido,alkylsulfonamido, amino, alkylamino, dialkylamino, amido, cycloalkyl,aryl, heterocycloalkyl, heteroaryl perhaloalkylcycloalkyl,hydroxyheterocycloalkyl, hydroxycycloalkyl, heterocycloalkylcarbonyl,and heterocycloalkylalkyl, any of which can be optionally substituted;and

R₂₃ is selected from the group consisting of hydrogen, deuterium,hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, saturated 3- to6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to6-membered heteroaryl.

In further embodiments, R₁₁ is hydrogen.

In further embodiments,

at least one of Z₁ or Z₂ is CR₁;

R₁ is selected from the group consisting of —Y₂-alkyl-N(R₄)R₅, hydrogen,deuterium, halogen, alkyl, alkenyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, acyl, carboxylalkyl, carboxyl, carbonyl,cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, thiolalkyl,sulfonyl, sulfonamido, alkylsulfonyl, amino, amido, alkylamino,dialkylamino, nitro, heterocycloalkyl, heterocycloalkyloxy,

heterocycloalkylcarbonylalkyl, and heterocycloalkylcarbonyl, any ofwhich can be optionally substituted with one or more substituentsselected from the group consisting of hydrogen, deuterium, halogen,alkyl, alkenyl, amidoalkyl, acyl, carboxylalkyl, hydroxyalkylcarbonyl,alkynylcarbonyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, carboxyl,cyano, hydroxy, alkoxy, oxo, sulfonamido, alkylsulfonyl, amino, amido,carbamate, dialkylamino, dialkylaminoalkyl, trisubstituted siloxy,cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, any of which may beoptionally substituted;

R₁₁ is selected from the group consisting of hydrogen, deuterium, alkyl,and cycloalkyl;

R₁₂, R₁₃, and R₁₄ are hydrogen;

R₁₆, R₁₇, R₁₉, and R₂₀ are hydrogen; and

R₂₃ is selected from the group consisting of hydrogen, deuterium,hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, and saturated 3- to6-membered cycloalkyl.

In further embodiments,

R₁ is selected from the group consisting of hydrogen, deuterium,fluorine, bromine, cyano, methyl, isopropyl,

ethylene,

trifluoromethyl, bromomethyl, hydroxymethyl, difluoromethoxy, methoxy,ethoxy, isopropoxy, hydroxy, nitro, acetyl, carboxyl, —CO₂CH₃,

—SO₂CH₃, —SO₂CH₂CH₃, SO₂CH₂CH₂CH₃, —SO₂NH₂,

amino, methylamino, dimethylamino,

R₁₈ is selected from the group consisting of hydrogen, deuterium,halogen, methyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, acetyl,hydroxymethyl, methoxymethyl, methoxy, isopropoxy, methylamino,dimethylamino, methylthio, cyanomethyl, cyanomethylthio, cyano, —SO₂CH₃,—SO₂CH(CH₃)₂, —SO₂CH₂CH(CH₃)₂, —SO₂NHCH₂CH₂CH₃, —SO₂CHF₂, —SO₂CF₃,

trifluoromethyl, trifluoromethylthio, difluoromethoxy, andtrifluoromethoxy;

R₂₂ is selected from the group consisting of hydrogen, deuterium,methyl, acetyl,

and

R₂₃ is selected from the group consisting of hydrogen, deuterium,methyl, ethyl, 3-pyridyl, and cyclopropyl.

In further embodiments of the present invention, R₁ is selected from thegroup consisting of hydrogen, halogen, cyano, methyl, isopropyl,

ethylene, trifluoromethyl, difluoromethoxy, methoxy, ethoxy, isopropoxy,hydroxy, carboxyl, —CO₂CH₃, —SO₂CH₃, —SO₂NH₂,

amino, methylamino, dimethylamino,

and

R₂₃ is methyl.

In further embodiments, R₁₁ is hydrogen.

In certain embodiments, disclosed herein are compounds having structuralFormula V:

or a salt thereof, wherein:

Z₂ is selected from the group consisting of N and CR₁₄;

R₁ is selected from the group consisting of heterocycloalkyl,alkoxyalkoxy, alkylsulfonylalkoxy, heterocycloalkyloxy,heterocycloalkylcarbonyl, alkoxyalkylamido, heterocycloalkylsulfonyl,alkoxyalkylsulfonamido, wherein said heterocycloalkyl,heterocycloalkyloxy, heterocycloalkylcarbonyl, andheterocycloalkylsulfonyl can be optionally substituted with one or moresubstituents selected from the group consisting hydrogen, alkyl, andoxo;

R₁₄, R₃₉, and R₄₀ are independently selected from the group consistingof hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, amino, andsaturated 3- to 7-membered cycloalkyl, any of which may be optionallysubstituted; and

R₁₈ is selected from the group consisting of alkyl, haloalkyl,perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio,haloalkylthio, and perhaloalkylthio.

In further embodiments, R₁ is selected from the group consisting of

In further embodiments, R₁₈ is selected from the group consisting ofisopropyl, tert-butyl, —CF₃, —OCF₃, —OCHF₂, and —SCF₃.

In further embodiments,

R₁ is selected from the group consisting of

R₁₃, R₁₄, R₁₆, R₁₇, and R₁₉ are hydrogen; and

R₁₈ is selected from the group consisting of isopropyl, tert-butyl,—CF₃, —OCF₃, —OCHF₂, and —SCF₃.

In further embodiments, disclosed herein is a compound selected from thegroup consisting of Examples 1 to 163, or a salt thereof.

In further embodiments, disclosed herein is a pharmaceutical compositioncomprising a compound as disclosed herein together with apharmaceutically acceptable carrier.

In further embodiments, disclosed herein is a method of treatment of aHIF pathway-mediated disease comprising the administration of atherapeutically effective amount of a compound as disclosed herein to apatient in need thereof.

In further embodiments, said disease is cancer.

In further embodiments, said cancer is selected from the groupconsisting of colon cancer, breast cancer, ovarian cancer, lung cancer,prostrate cancer; cancers of the oral cavity and pharynx (lip, tongue,mouth, larynx, pharynx), esophagus, stomach, small intestine, largeintestine, colon, rectum, liver and biliary passages; pancreas, bone,connective tissue, skin, cervix, uterus, corpus endometrium, testis,bladder, kidney and other urinary tissues, including renal cellcarcinoma (RCC); cancers of the eye, brain, spinal cord, and othercomponents of the central and peripheral nervous systems, as well asassociated structures such as the meninges; cancers of the thyroid andother endocrine glands; Hodgkin's disease, non-Hodgkin's lymphomas,multiple myeloma, hematopoietic malignancies including leukemias(Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL))and lymphomas including lymphocytic, granulocytic and monocytic;adrenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplasticastrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma,choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma,cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma,Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer,genitourinary tract cancers, glioblastoma multiforme, head and neckcancer, hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi'ssarcoma, large cell carcinoma, leiomyosarcoma, leukemias, liposarcoma,lymphatic system cancer, lymphomas, lymphangiosarcoma,lymphangioendotheliosarcoma, medullary thyroid carcinoma,medulloblastoma, meningioma mesothelioma, myelomas, myxosarcomaneuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma,epithelial ovarian cancer, papillary carcinoma, papillaryadenocarcinomas, paraganglioma, parathyroid tumours, pheochromocytoma,pinealoma, plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceousgland carcinoma, seminoma, skin cancers, melanoma, small cell lungcarcinoma, non-small cell lung carcinoma, squamous cell carcinoma, sweatgland carcinoma, synovioma, thyroid cancer, uveal melanoma, and Wilm'stumor.

In further embodiments, disclosed herein is a method of treatment of adisease caused by abnormal cell proliferation comprising theadministration of a therapeutically effective amount of a compound asdisclosed herein to a patient in need thereof.

In further embodiments, disclosed herein is a method of treatment of aHIF pathway-mediated disease comprising the administration of:

a. a therapeutically effective amount of a compound as disclosed herein;and

b. another therapeutic agent.

In further embodiments, disclosed herein is a method for achieving aneffect in a patient comprising the administration of a therapeuticallyeffective amount of a compound as disclosed herein to a patient, whereinthe effect is selected from the group consisting of preventing orreducing resistance to radiotherapy and chemotherapy, preventing orreducing tumor invasion and tumor metastasis, and preventing or reducingangiogenesis.

In certain embodiments, the compositions and methods disclosed hereinmay be used to inhibit HIF pathway activity, to downregulate HIF-1α(which is induced by hypoxia or genetic alterations, as well as invarious disease states, e.g. in persons with certain geneticbackgrounds), by increasing HIF-1α degradation, decreasing HIFheterodimer formation, increasing HIF-1α prolyl hydroxylation, and/or toreduce transcription of hypoxia response element (HRE) downstreamelements.

In certain embodiments, the compositions and methods disclosed hereinmay be used to reduce tumor growth, to inhibit neoangiogenesis (e.g., bydownregulating VEGF), to normalize tumor vasculature, to enhanceradiotherapy and chemotherapy, to prevent metastasis, to reduce tumorstem cell numbers, and to prevent induction of anaerobic cellularmetabolism.

In certain embodiments, the compositions and methods disclosed hereinmay be used to treat HIF-deregulated diseases with an inflammatorycomponent, such as cancers, stroke, and rheumatoid arthritis.

In certain embodiments, the compositions and methods disclosed hereinmay be used to treat HIF-deregulated diseases cardiovascular diseasessuch as cardiac arrhythmia and heart failure.

In certain embodiments, the compositions and methods disclosed hereinare useful for preventing or reducing resistance to radiotherapy andchemotherapy.

In certain embodiments, the compositions and methods disclosed hereinare useful for preventing or reducing tumor invasion and tumormetastasis.

In certain embodiments, the compositions and methods disclosed hereinare useful for preventing or reducing angiogenesis and disorders relatedto angiogenesis.

In certain embodiments, the compounds disclosed herein may be used as amedicament.

In further embodiments, said compounds which may be used as a medicamentinclude the compounds of Formula I, II, III, IV, and V, optionallyincluding any further limitation to the scope of said Formulas asdefined above. In further embodiments, said compounds may be selectedfrom the group consisting of Examples 1 to 163, or a salt thereof.

In certain embodiments, the disclosed are compounds for use in thetreatment of a HIF pathway-mediated disease.

In further embodiments, said compounds which may be used in thetreatment of a HIF pathway-mediated disease include the compounds ofFormula I, II, III, IV, and V, optionally including any furtherlimitation to the scope of said Formulas as defined above. In furtherembodiments, said compounds may be selected from the group consisting ofExamples 1 to 163, or a salt thereof.

In further embodiments, said disease is cancer.

In further embodiments, said cancer is selected from the groupconsisting of colon cancer, breast cancer, ovarian cancer, lung cancer,prostrate cancer; cancers of the oral cavity and pharynx (lip, tongue,mouth, larynx, pharynx), esophagus, stomach, small intestine, largeintestine, colon, rectum, liver and biliary passages; pancreas, bone,connective tissue, skin, cervix, uterus, corpus endometrium, testis,bladder, kidney and other urinary tissues, including renal cellcarcinoma (RCC); cancers of the eye, brain, spinal cord, and othercomponents of the central and peripheral nervous systems, as well asassociated structures such as the meninges; cancers of the thyroid andother endocrine glands; Hodgkin's disease, non-Hodgkin's lymphomas,multiple myeloma, hematopoietic malignancies including leukemias(Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL))and lymphomas including lymphocytic, granulocytic and monocytic;adrenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplasticastrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma,choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma,cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma,Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer,genitourinary tract cancers, glioblastoma multiforme, head and neckcancer, hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi'ssarcoma, large cell carcinoma, leiomyosarcoma, leukemias, liposarcoma,lymphatic system cancer, lymphomas, lymphangiosarcoma,lymphangioendotheliosarcoma, medullary thyroid carcinoma,medulloblastoma, meningioma mesothelioma, myelomas, myxosarcomaneuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma,epithelial ovarian cancer, papillary carcinoma, papillaryadenocarcinomas, paraganglioma, parathyroid tumours, pheochromocytoma,pinealoma, plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceousgland carcinoma, seminoma, skin cancers, melanoma, small cell lungcarcinoma, non-small cell lung carcinoma, squamous cell carcinoma, sweatgland carcinoma, synovioma, thyroid cancer, uveal melanoma, and Wilm'stumor.

In certain embodiments, disclosed herein are compounds for use in thetreatment of a disease caused by abnormal cell proliferation.

In certain embodiments, disclosed herein are compounds for use in thetreatment of HIF-deregulated diseases with an inflammatory component,such as cancers, stroke, and rheumatoid arthritis.

In certain embodiments, disclosed herein are compounds for use in thetreatment of HIF-deregulated cardiovascular diseases such as cardiacarrhythmia and heart failure.

In certain embodiments, disclosed herein are compounds for use in thetreatment of preventing or reducing resistance to radiotherapy andchemotherapy.

In certain embodiments, disclosed herein are compounds for use in theprevention or reduction of tumor invasion and tumor metastasis.

In certain embodiments, disclosed herein are compounds for use in theprevention or reduction of angiogenesis and disorders related toangiogenesis.

In further embodiments, said compounds which may be used in thetreatment of a disease caused by abnormal cell proliferation,HIF-deregulated diseases with an inflammatory component, such ascancers, stroke, and rheumatoid arthritis, HIF-deregulatedcardiovascular diseases such as cardiac arrhythmia and heart failure,for use in preventing or reducing resistance to radiotherapy andchemotherapy, prevention or reduction of tumor invasion and tumormetastasis, or prevention or reduction of angiogenesis and disordersrelated to angiogenesis include the compounds of Formula I, II, III, IV,and V, optionally including any further limitation to the scope of saidFormulas as defined above. In further embodiments, said compounds may beselected from the group consisting of Examples 1 to 163, or a saltthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1—Compounds of this invention inhibit the growth of diffuse largeB-cell lymphoma TMD8 cells as shown by reduced number of viable cellsfollowing treatment with Example 80.

FIG. 2—Compounds of this invention inhibit the growth of neuroblastomaNB-1 cells as shown by reduced number of viable cells followingtreatment with Examples 2 (FIG. 2A) and 80 (FIG. 2B).

FIG. 3—Compounds of this invention inhibit the growth of glioblastomaGli56 cells as shown by reduced number of viable cells followingtreatment with Example 80.

FIG. 4—Compounds of this invention inhibit the growth of glioblastomaD423 cells as shown by reduced number of viable cells followingtreatment with Examples 2 (FIG. 4A) and 80 (FIG. 4B).

FIG. 5—Compounds of this invention inhibit the growth of NB-1 xenograftsin vivo, daily oral treatment with 10 mg/kg of Example 80 reduces thetumor growth.

FIG. 6—Compounds of this invention inhibit the growth of H460 xenograftsin vivo, daily oral treatment with 150 mg/kg of Example 2 reduces thetumor growth.

FIG. 7—Compounds of this invention reduce the level of hypoxia in H460xenografts, daily oral treatment with 150 mg/kg of Example 2 reduce thelevel of hypoxia as measure by hypoxyprobe.

FIG. 8—Compounds of this invention reduce the level of the HIF regulatedgene carbonic anhydrase IX in H460 xenografts, daily oral treatment with150 mg/kg of Example 2 reduce the level of CAIX as shown by IHC.

FIG. 9—Compounds of this invention inhibit the growth of leukemiaOCI-AML3 cells as shown by reduced number of viable cells followingtreatment with Example 80.

FIG. 10—Compounds of this invention reduce disease burden in humanleukemia model, daily oral treatment with 10 mg/kg of Example 80 reducesdisease burden in OCI-AML3 models in NSG mice as measured by IVISimaging.

FIG. 11—Compounds of this invention prolong the survival in humanleukemia model, daily oral treatment with 10 mg/kg of Example 80 extendssurvival in OCI-AML3 models in NSG mice.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. When a conflict occurs, themeaning ascribed herein controls.

When ranges of values are disclosed, and the notation “from n1 . . . ton2” is used, where n1 and n2 are the numbers, then unless otherwisespecified, this notation is intended to include the numbers themselvesand the range between them. This range may be integral or continuousbetween and including the end values. By way of example, the range “from2 to 6 carbons” is intended to include two, three, four, five, and sixcarbons, since carbons come in integer units. Compare, by way ofexample, the range “from 1 to 3 μM (micromolar),” which is intended toinclude 1 μM, 3 μM, and everything in between to any number ofsignificant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety were the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—),(—C::C—)].Examples of suitable alkenyl radicals include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwisespecified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 6 carbon atoms. Alkyl groups may be optionally substituted as definedherein. Examples of alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, noyl and the like. The term “alkylene,” as used herein,alone or in combination, refers to a saturated aliphatic group derivedfrom a straight or branched chain saturated hydrocarbon attached at twoor more positions, such as methylene (—CH₂—). Unless otherwisespecified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —C—C—). Examples of alkynylradicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.Unless otherwise specified, the term “alkynyl” may include “alkynylene”groups.

The terms “amido” and “carbamoyl,” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C-amido” as used herein, alone or in combination, refers to a—C(O)N(RR′) group with R and R′ as defined herein or as defined by thespecifically enumerated “R” groups designated. The term “N-amido” asused herein, alone or in combination, refers to a RC(O)N(R′)— group,with R and R′ as defined herein or as defined by the specificallyenumerated “R” groups designated. The term “acylamino” as used herein,alone or in combination, embraces an acyl group attached to the parentmoiety through an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl,heteroaryl, and heterocycloalkyl, any of which may themselves beoptionally substituted. Additionally, R and R′ may combine to formheterocycloalkyl, either of which may be optionally substituted.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C₆H₄═ derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′, group-with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O-carboxy” group refers to a RC(O)O— group, where R is asdefined herein. A “C-carboxy” group refers to a —C(O)OR groups where Ris as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moietycontains from 3 to 12 carbon atom ring members and which may optionallybe a benzo fused ring system which is optionally substituted as definedherein. In certain embodiments, said cycloalkyl will comprise from 5 to7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and thelike. “Bicyclic” and “tricyclic” as used herein are intended to includeboth fused ring systems, such as decahydronaphthalene,octahydronaphthalene as well as the multicyclic (multicentered)saturated or partially unsaturated type, including spiro-ring fusedsystems. The bicyclic and tricyclic types of isomer are exemplified ingeneral by, bicyclo[1,1,1]pentane, camphor, adamantane,bicyclo[3,2,1]octane, and [4,4,1]-bicyclononane.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the radical. Dihalo and polyhaloalkyl radicals may have two ormore of the same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon radical,or combinations thereof, fully saturated or containing from 1 to 3degrees of unsaturation, consisting of the stated number of carbon atomsand from one to three heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N and S may be placed at any interior position of theheteroalkyl group. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 3 to 15 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom selectedfrom the group consisting of O, S, and N. In certain embodiments, saidheteroaryl will comprise from 5 to 7 carbon atoms. The term alsoembraces fused polycyclic groups wherein heterocyclic rings are fusedwith aryl rings, wherein heteroaryl rings are fused with otherheteroaryl rings, wherein heteroaryl rings are fused withheterocycloalkyl rings, or wherein heteroaryl rings are fused withcycloalkyl rings. Examples of heteroaryl groups include pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl,benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl,tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl,thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplarytricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyland the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated monocyclic, bicyclic, ortricyclic heterocyclic group containing at least one heteroatom as aring member, wherein each said heteroatom may be independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur In certainembodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatomsas ring members. In further embodiments, said hetercycloalkyl willcomprise from 1 to 2 heteroatoms as ring members. In certainembodiments, said hetercycloalkyl will comprise from 3 to 8 ring membersin each ring. In further embodiments, said hetercycloalkyl will comprisefrom 3 to 7 ring members in each ring. In yet further embodiments, saidhetercycloalkyl will comprise from 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sulfones,cyclic sulfonamides, sulfoxides, N-oxides of tertiary nitrogen ringmembers, and carbocyclic fused, benzo fused, and spiro-ring fused ringsystems; additionally, both terms also include systems where aheterocycle ring is fused to an aryl group, as defined herein, or anadditional heterocycle group. Examples of heterocycle groups includeaziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl,dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,tetrahydropyridinyl, piperidinyl, thiomorpholinyl, isothiazolidine, andthe like. The heterocycle groups may be optionally substituted unlessspecifically prohibited.

The term “hydrogen,” as used herein, refers to both protium (¹H) anddeuterium (²H). This definition extends to hydrogen atoms which appearin chemical structural drawings disclosed herein, including at siteswhere hydrogen atoms are not explicitly shown. For example, a chemicalstructure disclosed herein may include an ethyl group represented as

which includes five hydrogen atoms which are not explicitly drawn, anyof which can be protium (¹H) or deuterium (²H). This definition alsoextends to hydrogen atoms which form a part of a named chemicalsubstituent disclosed herein. For example, a generic chemical structuredisclosed herein may recite an aryl group, which encompasses specificembodiments such as a phenyl group, which comprises five hydrogen atoms,any of which can be protium (¹H) or deuterium (²H).

The term “deuterium enrichment” refers to the percentage ofincorporation of deuterium at a given position in a molecule in theplace of hydrogen. For example, deuterium enrichment of 1% at a givenposition means that 1% of molecules in a given sample contain deuteriumat the specified position. Because the naturally occurring distributionof deuterium is about 0.0156%, deuterium enrichment at any position in acompound synthesized using non-enriched starting materials is about0.0156%. The deuterium enrichment can be determined using conventionalanalytical methods known to one of ordinary skill in the art, includingmass spectrometry and nuclear magnetic resonance spectroscopy.

In certain embodiments, compounds disclosed herein are enriched withdeuterium. Carbon-hydrogen bond strength is directly proportional to theabsolute value of the ground-state vibrational energy of the bond. Thisvibrational energy depends on the mass of the atoms that form the bond,and increases as the mass of one or both of the atoms making the bondincreases. Since deuterium (D) has twice the mass of protium (¹H), a C-Dbond is stronger than the corresponding C—¹H bond. If a C—¹H bond isbroken during a rate-determining step in a chemical reaction (i.e. thestep with the highest transition state energy), then substituting adeuterium for that protium will cause a decrease in the reaction rate,including cases where a C—H bond is broken during metabolism of acompound disclosed herein. This phenomenon is known as the DeuteriumKinetic Isotope Effect (DKIE). The magnitude of the DKIE can beexpressed as the ratio between the rates of a given reaction in which aC—¹H bond is broken, and the same reaction where deuterium issubstituted for protium. The DKIE can range from about 1 (no isotopeeffect) to very large numbers, such as 50 or more. The deuterationapproach has the potential to slow the metabolism of the compoundsdisclosed herein. Various deuteration patterns can be used to (a) reduceor eliminate unwanted metabolites, (b) increase the half-life of theparent drug, (c) decrease the number of doses needed to achieve adesired effect, (d) decrease the amount of a dose needed to achieve adesired effect, (e) increase the formation of active metabolites, if anyare formed, (f) decrease the production of deleterious metabolites inspecific tissues, and/or (g) create a more effective drug and/or a saferdrug for polypharmacy, whether the polypharmacy be intentional or not.Deuterium can be introduced into a compound as disclosed herein bysynthetic techniques that employ deuterated reagents, wherebyincorporation rates are pre-determined; and/or by exchange techniques,wherein incorporation rates are determined by equilibrium conditions,and may be highly variable depending on the reaction conditions.Synthetic techniques where deuterium is directly and specificallyinserted by a deuterated reagent of known isotopic content, can yieldhigh deuterium abundance, but can be limited by the chemistry required.Exchange techniques, on the other hand, may yield lower deuteriumincorporation, often with the isotope being distributed over many siteson the molecule.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of any one of the formulas disclosed herein.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower,” as used herein, alone or in a combination, where nototherwise specifically defined, means containing from 1 to and including6 carbon atoms.

The term “lower aryl,” as used herein, alone or in combination, meansphenyl or naphthyl, either of which may be optionally substituted asprovided.

The term “lower heteroaryl,” as used herein, alone or in combination,means either 1) monocyclic heteroaryl comprising five or six ringmembers, of which between one and four said members may be heteroatomsselected from the group consisting of O, S, and N, or 2) bicyclicheteroaryl, wherein each of the fused rings comprises five or six ringmembers, comprising between them one to four heteroatoms selected fromthe group consisting of O, S, and N.

The term “lower cycloalkyl,” as used herein, alone or in combination,means a monocyclic cycloalkyl having between three and six ring members.Lower cycloalkyls may be unsaturated. Examples of lower cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or incombination, means a monocyclic heterocycloalkyl having between threeand six ring members, of which between one and four may be heteroatomsselected from the group consisting of O, S, and N. Examples of lowerheterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls maybe unsaturated.

The term “lower amino,” as used herein, alone or in combination, refersto —NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, lower alkyl, and lower heteroalkyl, any of whichmay be optionally substituted. Additionally, the R and R′ of a loweramino group may combine to form a five- or six-memberedheterocycloalkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′as defined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(O)₂NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(O)₂— group where X isa halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition ofsubstituted amino. Examples include trimethysilyl,tert-butyldimethylsilyl, triphenylsilyl and the like.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃),fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl,heteroaryl and heterocycloalkyl, any of which may be optionallysubstituted. Such R and R′ groups should be understood to be optionallysubstituted as defined herein. Whether an R group has a numberdesignation or not, every R group, including R, R′ and R^(n) where n=(1,2, 3, . . . n), every substituent, and every term should be understoodto be independent of every other in terms of selection from a group.Should any variable, substituent, or term (e.g. aryl, heterocycle, R,etc.) occur more than one time in a formula or generic structure, itsdefinition at each occurrence is independent of the definition at everyother occurrence. Those of skill in the art will further recognize thatcertain groups may be attached to a parent molecule or may occupy aposition in a chain of elements from either end as written. Thus, by wayof example only, an unsymmetrical group such as —C(O)N(R)— may beattached to the parent moiety at either the carbon or the nitrogen.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as d-isomers and 1-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentinvention includes all cis, trans, syn, anti, entgegen (E), and zusammen(Z) isomers as well as the appropriate mixtures thereof. Additionally,compounds may exist as tautomers; all tautomeric isomers are provided bythis invention. Additionally, the compounds disclosed herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position. When a group in a chemical formula is designated to be “abond,” the group reduces to a linkage between the groups to which it islinked in the formula. By way of example, in Formula I, when Y₂ is abond, it becomes a direct link between A and -alkyl-N(R₄)R₅, formingR₅(R₄)N-alkyl-A-Y₁—(B—(R₂)_(m))-D-E-(R₃)_(p).

As used herein, the term “modulate” means to increase or decrease theactivity of a target or the amount of a substance.

As used herein, the term “increase” or the related terms “increased,”“enhance” or “enhanced” refers to a statistically significant increase,and the terms “decreased,” “suppressed,” or “inhibited” to astatistically significant decrease. For the avoidance of doubt, anincrease generally refers to at least a 10% increase in a givenparameter, and can encompass at least a 20% increase, 30% increase, 40%increase, 50% increase, 60% increase, 70% increase, 80% increase, 90%increase, 95% increase, 97% increase, 99% or even a 100% increase overthe control, baseline, or prior-in-time value. Inhibition generallyrefers to at least a 10% decrease in a given parameter, and canencompass at least a 20% decrease, 30% decrease, 40% decrease, 50%decrease, 60% decrease, 70% decrease, 80% decrease, 90% decrease, 95%decrease, 97% decrease, 99% or even a 100% decrease over the controlvalue.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder” and“condition” (as in medical condition), in that all reflect an abnormalcondition of the human or animal body or of one of its parts thatimpairs normal functioning, is typically manifested by distinguishingsigns and symptoms, and causes the human or animal to have a reducedduration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single formulation (e.g., a capsule orinjection) having a fixed ratio of active ingredients or in multiple,separate dosage forms for each active ingredient. In addition, suchadministration also encompasses use of each type of therapeutic agent ina sequential manner. In either case, the treatment regimen will providebeneficial effects of the drug combination in treating the conditions ordisorders described herein.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder.This amount will achieve the goal of reducing or eliminating the saiddisease or disorder.

The term “therapeutically acceptable” refers to those compounds (orsalts, polymorphs, prodrugs, tautomers, zwitterionic forms, etc.) whichare suitable for use in contact with the tissues of patients withoutundue toxicity, irritation, and allergic response, are commensurate witha reasonable benefit/risk ratio, and are effective for their intendeduse.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis.

In the present invention, the term “radiation” means ionizing radiationcomprising particles or photons that have sufficient energy or canproduce sufficient energy via nuclear interactions to produce ionization(gain or loss of electrons). An exemplary and preferred ionizingradiation is an x-radiation. Means for delivering x-radiation to atarget tissue or cell are well known in the art. The amount of ionizingradiation needed in a given cell generally depends on the nature of thatcell. Means for determining an effective amount of radiation are wellknown in the art. Used herein, the term “an effective dose” of ionizingradiation means a dose of ionizing radiation that produces an increasein cell damage or death.

The term “radiation therapy” refers to the use of electromagnetic orparticulate radiation in the treatment of neoplasia and includes the useof ionizing and non-ionizing radiation.

As used herein, the term “patient” means all mammals including humans.Examples of patients include humans, cows, dogs, cats, goats, sheep,pigs, and rabbits. Preferably, the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound and N-oxides of amines or heterocyclic groups such as pyridine.

The term “metabolite” refers to a compound produced through biologicaltransformation of a compound following administration to a subject. Inorder to eliminate foreign substances such as therapeutic agents, theanimal body expresses various enzymes, such as the cytochrome P₄₅₀enzymes (CYPs), esterases, proteases, reductases, dehydrogenases, andmonoamine oxidases, to react with and convert these foreign substancesto more polar intermediates or metabolites for renal excretion. Suchmetabolic reactions frequently involve the oxidation of acarbon-hydrogen (C—H) bond to either a carbon-oxygen (C—O) or acarbon-carbon (C—C)-bond, N-oxidation, or covalent bonding of a polarmolecule or functional group (such as sulfate, glucuronic acid,glutathione, or glycine, to the therapeutic agent. The resultantmetabolites may be stable or unstable under physiological conditions,and can have substantially different pharmacokinetic, pharmacodynamic,and acute and long-term toxicity profiles relative to the parentcompounds. Certain compounds disclosed herein may, after administrationto a subject result in formation of metabolites, which in some caseshave biological activity as HIF pathway modulators or activity againstother biological systems. In certain embodiments, metabolites of thecompounds disclosed herein include N-oxides, particularly N-oxides ofheterocyclic groups such as pyridine. In further embodiments,metabolites of compounds disclosed herein may themselves havesubstantial activity as HIF pathway inhibitors.

The compounds disclosed herein can exist as therapeutically acceptablesalts. Suitable acid addition salts include those formed with bothorganic and inorganic acids, and will normally be pharmaceuticallyacceptable. However, salts of non-pharmaceutically acceptable salts maybe of utility in the preparation and purification of the compound inquestion. Basic addition salts may also be formed and bepharmaceutically acceptable. Representative acid addition salts includeacetate, adipate, alginate, L-ascorbate, aspartate, benzoate,benzenesulfonate (besylate), bisulfate, butyrate, camphorate,camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate,glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate,DL-mandelate, mesitylenesulfonate, methanesulfonate,naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate,picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate,tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate,glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), andundecanoate. Also, basic groups in the compounds disclosed herein can bequaternized with methyl, ethyl, propyl, and butyl chlorides, bromides,and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl,lauryl, myristyl, and steryl chlorides, bromides, and iodides; andbenzyl and phenethyl bromides. For a more complete discussion of thepreparation and selection of salts, refer to Pharmaceutical Salts:Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich,Switzerland, 2002).

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid. Examples ofacids which can be employed to form therapeutically acceptable additionsalts include inorganic acids such as hydrochloric, hydrobromic,sulfuric, and phosphoric, and organic acids such as oxalic, maleic,succinic, and citric. Salts can also be formed by coordination of thecompounds with an alkali metal or alkaline earth ion.

Basic addition salts can be prepared during the final isolation andpurification of the compounds, often by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium (e.g., NaOH), potassium (e.g., KOH), calcium (includingCa(OH)₂), magnesium (including Mg(OH)₂ and magnesium acetate), zinc,(including Zn(OH)₂ and zinc acetate) and aluminum, as well as nontoxicquaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine,choline hydroxide, hydroxyethyl morpholine, hydroxyethyl pyrrolidone,imidazole, n-methyl-d-glucamine, N, N′-dibenzylethylenediamine, N,N′-diethylethanolamine, N, N′-dimethylethanolamine, triethanolamine, andtromethamine. Basic amino acids such as 1-glycine and 1-arginine, andamino acids which may be zwitterionic at neutral pH, such as betaine(N,N,N-trimethylglycine) are also contemplated.

Salts disclosed herein may combine in 1:1 molar ratios, and in fact thisis often how they are initially synthesized. However, it will berecognized by one of skill in the art that the stoichiometry of one ionin a salt to the other may be otherwise. Salts shown herein may be, forthe sake of convenience in notation, shown in a 1:1 ratio; all possiblestoichiometric arrangements are encompassed by the scope of the presentinvention.

The terms, “polymorphs” and “polymorphic forms” and related terms hereinrefer to crystal forms of the same molecule, and different polymorphsmay have different physical properties such as, for example, meltingtemperatures, heats of fusion, solubilities, dissolution rates and/orvibrational spectra as a result of the arrangement or conformation ofthe molecules in the crystal lattice. The differences in physicalproperties exhibited by polymorphs affect pharmaceutical parameters suchas storage stability, compressibility and density (important informulation and product manufacturing), and dissolution rates (animportant factor in bioavailability). Differences in stability canresult from changes in chemical reactivity (e.g. differential oxidation,such that a dosage form discolors more rapidly when comprised of onepolymorph than when comprised of another polymorph) or mechanicalchanges (e.g. tablets crumble on storage as a kinetically favoredpolymorph converts to thermodynamically more stable polymorph) or both(e. g., tablets of one polymorph are more susceptible to breakdown athigh humidity). As a result of solubility/dissolution differences, inthe extreme case, some polymorphic transitions may result in lack ofpotency or, at the other extreme, toxicity. In addition, the physicalproperties of the crystal may be important in processing, for example,one polymorph might be more likely to form solvates or might bedifficult to filter and wash free of impurities (i.e., particle shapeand size distribution might be different between polymorphs).

Polymorphs of a molecule can be obtained by a number of methods, asknown in the art. Such methods include, but are not limited to, meltrecrystallization, melt cooling, solvent recrystallization, desolvation,rapid evaporation, rapid cooling, slow cooling, vapor diffusion andsublimation.

While it may be possible for the compounds and prodrugs disclosed hereinto be administered as the raw chemical, it is also possible to presentthem as a pharmaceutical formulation. Accordingly, provided herein arepharmaceutical formulations which comprise one or more of certaincompounds and prodrugs disclosed herein, or one or more pharmaceuticallyacceptable salts, esters, amides, or solvates thereof, together with oneor more pharmaceutically acceptable carriers thereof and optionally oneor more other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art; e.g., in Remington'sPharmaceutical Sciences. The pharmaceutical compositions disclosedherein may be manufactured in any manner known in the art, e.g., bymeans of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal,intranasal, rectal and topical (including dermal, buccal, sublingual andintraocular) administration although the most suitable route may dependupon for example the condition and disorder of the recipient. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy.Typically, these methods include the step of bringing into association acompound of the subject invention or a pharmaceutically acceptable salt,ester, amide, prodrug or solvate thereof (“active ingredient”) with thecarrier which constitutes one or more accessory ingredients. In general,the formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the compounds and prodrugs disclosed herein suitable fororal administration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds and prodrugs may bedissolved or suspended in suitable liquids, such as fatty oils, liquidparaffin, or liquid polyethylene glycols. In addition, stabilizers maybe added. Dragee cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses.

The compounds and prodrugs may be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundsand prodrugs which may contain antioxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe compounds and prodrugs to allow for the preparation of highlyconcentrated solutions.

In addition to the formulations described previously, a compound orprodrug as disclosed herein may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds and prodrugsmay be formulated with suitable polymeric or hydrophobic materials (forexample as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds and prodrugs may also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds and prodrugs disclosed herein may be administeredtopically, that is by non-systemic administration. This includes theapplication of a compound disclosed herein externally to the epidermisor the buccal cavity and the instillation of such a compound into theear, eye and nose, such that the compound does not significantly enterthe blood stream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient for topical administration maycomprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

For administration by inhalation, compounds and prodrugs may beconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, the compounds and prodrugsdisclosed herein may take the form of a dry powder composition, forexample a powder mix of the compound and a suitable powder base such aslactose or starch. The powder composition may be presented in unitdosage form, in for example, capsules, cartridges, gelatin or blisterpacks from which the powder may be administered with the aid of aninhalator or insufflator.

Intranasal delivery, in particular, may be useful for deliveringcompounds to the CNS. It had been shown that intranasal drugadministration is a noninvasive method of bypassing the blood-brainbarrier (BBB) to deliver neurotrophins and other therapeutic agents tothe brain and spinal cord. Delivery from the nose to the CNS occurswithin minutes along both the olfactory and trigeminal neural pathways.Intranasal delivery occurs by an extracellular route and does notrequire that drugs bind to any receptor or undergo axonal transport.Intranasal delivery also targets the nasal associated lymphatic tissues(NALT) and deep cervical lymph nodes. In addition, intranasallyadministered therapeutics are observed at high levels in the bloodvessel walls and perivascular spaces of the cerebrovasculature. Usingthis intranasal method in animal models, researchers have successfullyreduced stroke damage, reversed Alzheimer's neurodegeneration, reducedanxiety, improved memory, stimulated cerebral neurogenesis, and treatedbrain tumors. In humans, intranasal insulin has been shown to improvememory in normal adults and patients with Alzheimer's disease. Hanson LR and Frey W H, 2nd, J Neuroimmune Pharmacol. 2007 March; 2(1):81-6.Epub 2006 Sep. 15.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations described above may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds and prodrugs may be administered orally or via injection at adose of from 0.1 to 500 mg/kg per day. The dose range for adult humansis generally from 5 mg to 2 g/day. Tablets or other forms ofpresentation provided in discrete units may conveniently contain anamount of one or more compound or prodrug which is effective at suchdosage or as a multiple of the same, for instance, units containing 5 mgto 500 mg, usually around 10 mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The compounds and prodrugs can be administered in various modes, e.g.orally, topically, or by injection. The precise amount of compoundadministered to a patient will be the responsibility of the attendantphysician. The specific dose level for any particular patient willdepend upon a variety of factors including the activity of the specificcompound employed, the age, body weight, general health, sex, diets,time of administration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of theindication or condition being treated. Also, the route of administrationmay vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least oneof the compounds and prodrugs described herein (or a pharmaceuticallyacceptable salt or ester thereof) in combination with anothertherapeutic agent. By way of example only, if one of the side effectsexperienced by a patient upon receiving one of the compounds herein forthe treatment of cancer is nausea, then it may be appropriate toadminister an antiemetic agent in combination. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein may be enhanced by administration of an adjuvant (i.e., by itselfthe adjuvant may only have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, by way of example only, thebenefit of experienced by a patient may be increased by administeringone of the compounds described herein with another therapeutic agent(which also includes a therapeutic regimen) that also has therapeuticbenefit. By way of example only, in a treatment for cancer involvingadministration of one of the compounds described herein, increasedtherapeutic benefit may result by also providing the patient withanother therapeutic agent for cancer. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

The compounds disclosed herein, including compounds of Formula I, arealso useful as chemo- and radio-sensitizers for cancer treatment. Theyare useful for the treatment of mammals who have previously undergone orare presently undergoing or will be undergoing treatment for cancer.Such other treatments include chemotherapy, radiation therapy, surgeryor immunotherapy, such as cancer vaccines.

The instant compounds are particularly useful in combination withtherapeutic, anti-cancer and/or radiotherapeutic agents. Thus, thepresent invention provides a combination of the presently compounds ofFormula I with therapeutic, anti-cancer and/or radiotherapeutic agentsfor simultaneous, separate or sequential administration. The compoundsof this invention and the other anticancer agent can act additively orsynergistically. A synergistic combination of the present compounds andanother anticancer agent might allow the use of lower dosages of one orboth of these agents and/or less frequent dosages of one or both of theinstant compounds and other anticancer agents and/or to administer theagents less frequently can reduce any toxicity associated with theadministration of the agents to a subject without reducing the efficacyof the agents in the treatment of cancer. In addition, a synergisticeffect might result in the improved efficacy of these agents in thetreatment of cancer and/or the reduction of any adverse or unwanted sideeffects associated with the use of either agent alone.

The therapeutic agent, anti-cancer agent and/or radiation therapy can beadministered according to therapeutic protocols well known in the art.It will be apparent to those skilled in the art that the administrationof the therapeutic agent, anti-cancer agent and/or radiation therapy canbe varied depending on the disease being treated and the known effectsof the anti-cancer agent and/or radiation therapy on that disease. Also,in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., anti-neoplastic agent or radiation) on thepatient, and in view of the observed responses of the disease to theadministered therapeutic agents, and observed adverse affects.

Dosage ranges for x-rays range from daily doses of 50 to 200 roentgensfor prolonged periods of time (3 to 4 weeks), to single doses of 2000 to6000 roentgens. Dosage ranges for radioisotopes vary widely, and dependon the half-life of the isotope, the strength and type of radiationemitted, and the uptake by the neoplastic cells.

Any suitable means for delivering radiation to a tissue may be employedin the present invention. Common means of delivering radiation to atissue is by an ionizing radiation source external to the body beingtreated. Alternative methods for delivering radiation to a tissueinclude, for example, first delivering in vivo a radiolabeled antibodythat immunoreacts with an antigen of the tumor, followed by deliveringin vivo an effective amount of the radio labeled antibody to the tumor.In addition, radioisotopes may be used to deliver ionizing radiation toa tissue or cell. Additionally, the radiation may be delivered by meansof a radiomimetic agent. As used herein a “radiomimetic agent” is achemotherapeutic agent, for example melphalan, that causes the same typeof cellular damage as radiation therapy, but without the application ofradiation.

In one embodiment, the compounds of formula I can be administered incombination with one or more agent selected from aromatase inhibitors,anti-estrogens, anti-progesterons, anti-androgens, or gonadorelinagonists, anti-inflammatory agents, antihistamines, anti-cancer agent,inhibitors of angiogenesis, topoisomerase 1 and 2 inhibitors,microtubule active agents, alkylating agents, antineoplastic,antimetabolite, dacarbazine (DTIC), platinum containing compound, lipidor protein kinase targeting agents, protein or lipid phosphatasetargeting agents, anti-angiogenic agents, agents that induce celldifferentiation, bradykinin 1 receptor and angiotensin II antagonists,cyclooxygenase inhibitors, heparanase inhibitors, lymphokines orcytokine inhibitors, bisphosphanates, rapamycin derivatives,anti-apoptotic pathway inhibitors, apoptotic pathway agonists, PPARagonists, HSP90 inhibitor, smoothened antagonist, inhibitors of Rasisoforms, telomerase inhibitors, protease inhibitors, metalloproteinaseinhibitors, aminopeptidase inhibitors, imununomodulators, therapeuticantibody and a protein kinase inhibitor, e.g., a tyrosine kinase orserine/threonine kinase inhibitor.

In another embodiment is provided a combination of a compound of formulaI and an anti-cancer agent for simultaneous, separate or sequentialadministration.

Examples of cancer agents or chemotherapeutic agents for use incombination with the compounds as disclosed herein can be found inCancer Principles and Practice of Oncology by V.T. Devita and S. Hellman(editors), 6th edition (Feb. 15, 2001), Lippincott Williams & WilkinsPublishers, and WO 2006/061638. A person of ordinary skill in the artwould be able to discern which combinations of agents would be usefulbased on the particular characteristics of the drugs and the cancerinvolved. Classes of such agents include the following: estrogenreceptor modulators, androgen receptor modulators, retinoid receptormodulators, cytotoxic/cytostatic agents, antiproliferative agents,prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors andother angiogenesis inhibitors, HIV protease inhibitors, reversetranscriptase inhibitors, inhibitors of cell proliferation and survivalsignaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics,γ-secretase inhibitors, agents that interfere with receptor tyrosinekinases (RTKs), agents that interfere with cell cycle checkpoints, PARPinhibitors, HDAC inhibitors, Smo antagonists (HH inhibitors), HSP90inhibitors, CYP17 inhibitors, 3rd generation AR antagonists, JAKinhibitors e.g. Ruxolitinib (trade name Jakafi, and BTK kinaseinhibitors.

Anticancer agents suitable for use in the combination therapy withcompounds as disclosed herein include, but are not limited to:

1) alkaloids and natrual product drugs, including, microtubuleinhibitors (e.g., Vincristine, Vinblastine, and Vindesine, andvinorelbine etc.), microtubule stabilizers (e.g., Paclitaxel [Taxol],and Docetaxel, Taxotere, etc.), and chromatin function inhibitors,including, topoisomerase inhibitors, such as, epipodophyllotoxins (e.g.,Etoposide [VP-161, and Teniposide [VM-261, etc.), and agents that targettopoisomerase I (e.g., Camptothecin, topotecan (Hycamtin) and Irinotecan[CPT-11], rubitecan (Orathecin) etc.);

2) covalent DNA-binding agents [alkylating agents], including, nitrogenmustards (e.g., Mechloretharnine, chlormethine, Chlorambucil,Cyclophosphamide, estramustine (Emcyt, Estracit), ifosfamide,Ifosphamide, melphalan (Alkeran) etc.); alkyl sulfonates like Busulfan[Myleran], nitrosoureas (e.g., Carmustine or BCNU(bis-chloroethylnitrosourea), fotemustine Lomustine, and Semustine,streptozocin etc.), and other alkylating agents (e.g., Dacarbazine,procarbazine ethylenimine/methylmelamine, thriethylenemelamine (TEM),triethylene thiophosphoramide (thiotepa), hexamethylmelamine (HMM,altretamine), and Mitocycin, uramustine etc.) including Temozolomide(brand names Temodar and Temodal and Temcad), altretamine (also hexalen)and mitomycin;

3) noncovalent DNA-binding agents [antitumor antibiotics], includingnucleic acid inhibitors (e.g., Dactinomycin [Actinomycin Dl, etc.),anthracyclines (e.g., Daunorubicin [Daunomycin, and Cerubidine],Doxorubicin [Adrianycin], epirubicin (Ellence), and Idarubicin[Idamycin], valrubicin (Valstar) etc.), anthracenediones (e.g.,anthracycline analogues, such as, [Mitoxantrone], etc.), bleomycins(Blenoxane), etc., amsacrine and plicamycin (Mithramycin), dactinomycin,mitomycin C:

4) antimetabolites, including, antifolates (e.g., Methotrexate, Folex,aminopterin, pemetrexed, raltitrexed and Mexate, trimetrexate etc.),purine antimetabolites (e.g., 6-Mercaptopurine[6-MP, Purinethol],cladribine, 6-Thioguanine [6-TG], clofarabine (Clolar, Evoltra),Azathioprine, Acyclovir, Fludarabine or fludarabine phosphate (Fludara)Ganciclovir, Chlorodeoxyadenosine, 2-Chlorodeoxyadenosine [CdA], and2′-Deoxycoformycin [Pentostatin], etc.), pyrimidine antagonists (e.g.,fluoropyrimidines [e.g., 5-fluorouracil (Adrucil), 5-fluorodeoxyuridine(FdUrd) (Floxuridine)], capecitabine Carmofur or HCFU(1-hexylcarbamoyl-5-fluorouracil), tegafur etc.), gemcitabine (Gemzar),and cytosine arabinosides (e.g., Cytarabine, or cytosine arabinoside,Cytosar [ara-C] and Fludarabine, 5-azacytidine,2,2′-difluorodeoxycytidine etc.) and hydroxyurea (Hydrea and Droxia,hydroxycarbamide), plus lonidamine;

5) enzymes, including, L-asparaginase and derivatives such aspegaspargase (Oncaspar), and RNAse A;

7) hormones and antagonists, Examples of hormones and hormonal analoguesbelieved to be useful in the treatment of neoplasms include, but are notlimited to antiestrogens and selective estrogen receptor modulators(SERMs), such as tamoxifen, toremifene, raloxifene, iodoxyfene,droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone;anti-androgens; such as enzalutamide (Xtandi®), flutamide, nilutamide,bicalutamide, leuprolide, and goserelin, and cyproterone acetate;adrenocorticosteroids such as prednisone and prednisolone;aminoglutethimide, finasteride and other aromatase inhibitors such asanastrozole, letrazole, vorazole, exemestane, formestanie, andfadrozole; Estrogen Receptor Downregulators (EROs) including Faslodex orfulvestrant, progestrins such as megestrol acetate; Sa-reductaseinhibitors such as finasteride and dutasteride; andgonadotropin-releasing hormones (GnRH) and analogues thereof, such asLeutinizing Hormone-releasing Hormone (LHRH) agonists and antagonistssuch as goserelin luprolide, leuprorelin and buserelin.

8) platinum compounds (e.g., Cisplatin and Carboplatin, oxaliplatin,Triplatin tetranitrate (rINN; also known as BBR3464), eptaplatin,lobaplatin, nedaplatin, or satraplatin etc.);

9) retinoids such as bexarotene (Targretin).

10) proteasome inhibitors such as bortezomib and carfilzomib(Kyprolis®).

11) anti-mitotics in addition to diterpenoids and vinca alkaloidsinclude polo-like kinase (PLK) inhibitors, mitotic kinesin spindleprotein (KSP) inhibitors including SB-743921 and MK-833 and CenpEinhibitors.

12) monoclonal antibodies, including cancer immunotherapy monoclonalantibodies and humanized monoclonal antibodies. For example:

12-a) cancer immunotherapy monoclonal antibodies include agents selectedfrom the group consisting of Trastuzumab (Herceptin®), an example of ananti-erbB2 antibody inhibitor of growth factor function; cetuximab(Erbitux™, C225), an example of an anti-erbB1 antibody inhibitor ofgrowth factor function; bevacizumab (Avastin®), an example of amonoclonal antibody directed against VEGFR; rituximab, alemtuzumab,gemtuzumab, panitumumab, tositumomab, pertuzumab.

12-b) humanized monoclonal antibodies with therapeutic potential aschemotherapeutic agents in combination include: alemtuzumab, apolizumab,aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumabmertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol,cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab,epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin,inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab,mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab,nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab,pascolizumab, pecfusituzumab, pectuzumab, pertuzumab (Perjeta®),pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab,resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab,sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab,tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin,tucusituzumab, umavizumab, urtoxazumab, and visilizumab;

13) monoclonal antibodies conjugated with anticancer drugs, toxins,and/or radionuclides, etc. gemtuzumab ozogamicin (MYLOTARG), trastuzumabemtansine (T-DM1)/ado-trastuzumab emtansine (Kadcyla®);

14) biological response modifiers (e.g., interferons [e.g., IFN-.alpha.,etc.] and interleukins [e.g., IL-2, etc.], denileukin diftitox (Ontak),G-CSF, GM-CSF: etc.);

15) adoptive immunotherapy; Immunotherapeutic regimens include ex-vivoand in-vivo approaches to increasing immunogenicity of patient tumorcells such as transfection with cytokines (eg. IL-2 or aldesleukin,IL-4, GMCFS), as well as IL-1, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9,IL-10, IL-11, IL-12, and active biological variants approaches toincrease T-cell activity, approaches with transfected immune cells andapproaches with antiidiotypic antibodies;

16) immunosuppressant selected from the group consisting of fingolimod,cyclosporine A, Azathioprine, dexamethasone, tacrolimus, sirolimus,pimecrolimus, mycophenolate salts, everolimus, basiliximab, daclizumab,anti-thymocyte globulin, anti-lymphocyte globulin, and tofacitinib.Agents capable of enhancing antitumor immune responses, such as CTLA4(cytotoxic lymphocyte antigen 4) antibodies such as Ipilimumab (MDX-010or MDX-101, Yervoy) and tremelimumab, and other agents capable ofblocking CTLA4;

17) immune modulators, for use in conjunction with the compound asdisclosed herein include staurosprine and macrocyclic analogs thereof,including UCN-01, CEP-701 and midostaurin; squalamine; DA-9601;alemtuzumab; interferons (e.g. IFN-α, IFN-b etc.); altretamine(Hexalen®); SU 101 or leflunomide; imidazoquinolines such as resiquimod,imiquimod, anti-PD-1 human monoclonal antibodies MDX-1106 (also known asBMS-936558), MK3475, CT-011, and AMP-224, anti-PD-L1 monoclonalantibodies such as MDX-1105, anti-OX40 monoclonal antibodies, and LAG3fusion proteins such as IMP321g, anti-B7-H3 monoclonal antibodies suchas MGA271, anti-B7-H4 monoclonal antibodies, and anti-TIM3 monoclonalantibodies;

18) hematopoietic growth factors;

19) agents that induce tumor cell differentiation (e.g., tretinoin (alltrans retinoic acid) (brand names Aberela, Airol, Renova, Atralin,Retin-A, Avita, Retacnyl, Refissa, or Stieva-A));

20) gene therapy techniques; such as gene therapy vaccines, for example,ALLOVECTIN®, LEUVECTIN®, and V AXID®;

21) antisense therapy techniques;

22) tumor vaccines; include Avicine®; oregovomab (OvaRex®); Theratope®(STn-KLH); Melanoma Vaccines; Gl-4000 series (GI-4014, Gl-4015, andGl-4016), which are directed to five mutations in the Ras protein;GlioVax-1; MelaVax; Advexin® or INGN-201; Sig/E7/LAMP-1, encoding HPV-16E7; MAGE-3 Vaccine or M3TK; HER-2VAX; ACTIVE, which stimulates T-cellsspecific for tumors; GM-CSF cancer vaccine; and Listeriaonocytogenes-based vaccines;

23) therapies directed against tumor metastases (e.g., Batimistat,etc.);

24) inhibitors of angiogenesis. Receptor kinase angiogenesis inhibitorsmay also find use in the present invention. Inhibitors of angiogenesisrelated to VEGFR and TIE-2. Other inhibitors may be used in combinationwith the compounds of the invention. For example, anti-VEGF antibodies,which do not recognize VEGFR (the receptor tyrosine kinase), but bind tothe ligand; small molecule inhibitors of integrin (alphav beta3) thatinhibit angiogenesis; endostatin and angiostatin (non-RT) may also proveuseful in combination with the compounds of the invention. One exampleof a VEGFR antibody is bevacizumab (Avastin®). Other anti-angiogeniccompounds include acitretin, fenretinide, thalidomide, zoledronic acid,angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin,halofuginone, rebimastat, removab, Lenalidomid (Revlimid), squalamine,Vitaxin, and pomalidomide (Pomalyst®);

25) signal transduction pathway inhibitors. Signal transduction pathwayinhibitors are those inhibitors which block or inhibit a chemicalprocess which evokes an intracellular change. As used herein thesechanges include, but are not limited to, cell proliferation ordifferentiation or survival. Signal transduction pathway inhibitorsuseful in the present invention include, but are not limited to,inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases,SH2/SH3 domain blockers, serine/threonine kinases, phosphatidylinositoi-3-0H kinases, myoinositol signaling, and Ras oncogenes. Signaltransduction pathway inhibitors may be employed in combination with thecompounds of the invention;

26) kinase inhibitors, including tyrosine kinases, serine/threoninekinases, kinases involved in the IGF-1 R signaling axis, PI3k/AKT/mTORpathway inhibitors, and SH2/SH3 domain blockers. Examples of relevantkinases include:

26-a) tyrosine kinases. Several protein tyrosine kinases catalyze thephosphorylation of specific tyrosine residues in various proteinsinvolved in the regulation of cell growth. Such protein tyrosine kinasescan be broadly classified as receptor or non-receptor kinases. Receptortyrosine kinase inhibitors which may be combined with the compounds ofthe invention include those involved in the regulation of cell growth,which receptor tyrosine kinases are sometimes referred to as “growthfactor receptors.” Examples of growth factor receptor inhibitors,include but are not limited to inhibitors of: insulin growth factorreceptors (IGF-1 R, IR and IRR); epidermal growth factor familyreceptors (EGFR, ErbB2, and ErbB4); platelet derived growth factorreceptors (PDGFRs), vascular endothelial growth factor receptors(VEGFRs), tyrosine kinase with immunoglobulin-like and epidermal growthfactor homology domains (TIE-2), macrophage colony stimulating factor(c-FMS), c-KIT, cMET, fibroblast growth factor receptors (FGFRs),hepatocyte growth factor receptors (HGFRs), Trk receptors (TrkA, TrkB,and TrkC), ephrin (Eph) receptors, the RET protooncogene, and HumanEpidermal Growth Factor Receptor 2 (HER-2). Examples of small moleculeinhibitors of epidermal growth factor receptors include but are notlimited to gefitinib, lapatinib (Tykerb®), erlotinib (Tarceva®),afatinib (Gilotrif®, Tomtovok®, and Tovok®), and .lmatinib (Gleevec®) isone example of a PDGFR inhibitor. Examples of VEGFR inhibitors includepazopanib (Votrient™), Vandetanib (ZD6474), AZD2171, vatalanib(PTK-787), Axitinib (AG013736; Inlyta®), dovitinib (CHIR-258),cabozantinib (Cometriq®), sunitinib, and sorafenib. Protein Kinase C(PKC) inhibitors, such as ruboxistaurin, AEB071 (Sotrastaurin) LY-317615and perifosine. Examples of small molecule inhibitors of multipletyrosine kinases include but are not limited to bosutinib (Bosulif®)and. Other kinase inhibitors include but are not limited to BIBF-1120,dasatinib (sprycel), pelitinib, nilotinib, and lestaurtinib (CEP-701).Tyrosine kinases that are not transmembrane growth factor receptorkinases are termed non-receptor, or intracellular tyrosine kinases.Inhibitors of non-receptor tyrosine kinases are sometimes referred to as“anti-metastatic agents” and are useful in the present invention.Targets or potential targets of anti-metastatic agents, include, but arenot limited to, c-Src, Lck, Fyn, Yes, Jak, Abl kinase (c-Abl andBcr-Abl), FAK (focal adhesion kinase) and Bruton's tyrosine kinase(BTK). Examples of small molecule inhibitors of Bcr-Abl include but arenot limited to ponatinib (Iclusig®). Non-receptor kinases and agents,which inhibit non-receptor tyrosine kinase function, are described inSinha, S. and Corey, S. J., J. Hematother. Stem Cell Res. (1999) 8465-80; and Bolen, J. B. and Brugge, J. S., Annu. Rev. of Immunol.(1997) 15 371-404;

26-b) serine/threonine kinases. Inhibitors of serine/threonine kinasesmay also be used in combination with the compounds of the invention inany of the compositions and methods described above. Examples ofserine/threonine kinase inhibitors that may also be used in combinationwith a compound of the present invention include, but are not limitedto, polo-like kinase inhibitors (Pik family e.g., Plk1, Plk2, and Plk3),which play critical roles in regulating processes in the cell cycleincluding the entry into and the exit from mitosis; MAP kinase cascadeblockers, which include other Ras/Raf kinase inhibitors, mitogen orextracellular regulated kinases (MEKs), and extracellular regulatedkinases (ERKs); Aurora kinase inhibitors (including inhibitors of AuroraA and Aurora B); protein kinase C (PKC) family member blockers,including inhibitors of PKC subtypes (alpha, beta, gamma, epsilon, mu,lambda, iota, zeta); inhibitors of kappa-B (lkB) kinase family(IKK-alpha, IKK-beta); PKB/Akt kinase family inhibitors; and inhibitorsof TGF-beta receptor kinases. Examples of Plk inhibitors are describedin PCT Publication No. WO04/014899 and WO07/03036;

26-c) kinases involved in the IGF-1 R signaling axis. Inhibitors ofkinases involved in the IGF-1 R signaling axis may also be useful incombination with the compounds of the present invention. Such inhibitorsinclude but are not limited to inhibitors of JNK1/2/3, PI3K, AKT andMEK, and 14.3.3 signaling inhibitors;

26-d) PI3k/AKT/mTOR pathway inhibitors, including GDC-0941, XL-147,GSK690693 and temsirolimus, SF-1126 (PI3K inhibitor,), BEZ-235 (PI3Kinhibitor);

26-e) SH2/SH3 domain blockers. SH2/SH3 domain blockers are agents thatdisrupt SH2 or SH3 domain binding in a variety of enzymes or adaptorproteins including, but not limited to, PI3-K p85 subunit, Src familykinases, adaptor molecules (She, Crk, Nck, Grb2) and Ras-GAP. Examplesof Src inhibitors include, but are not limited to, dasatinib andBMS-354825 (J. Med. Chern. (2004) 4 7 6658-6661);

27) inhibitors of Ras oncogenes. Inhibitors of Ras oncogene may also beuseful in combination with the compounds of the present invention. Suchinhibitors include, but are not limited to, inhibitors offarnesyltransferase, geranyl-geranyl transferase, and CAAX proteases aswell as anti-sense oligonucleotides, ribozymes and immunotherapy. Suchinhibitors have been shown to block Ras activation in cells containingmutant Ras, thereby acting as antiproliferative agents.

28) Raf/MEK/ERK pathway modulators. The Raf/MEK/ERK pathway is criticalfor cell survival, growth, proliferation and tumorigenesis. Li, Nanxin,et al. “B-Raf kinase inhibitors for cancer treatment.” Current Opinionin Investigational Drugs. Vol. 8, No. 6 (2007): 452-456. Raf kinasesexist as three isoforms, A-Raf, B-Raf and C-Raf. Among the threeisoforms, studies have shown that B-Raf functions as the primary MEKactivator. B-Raf is one of the most frequently mutated genes in humancancers. B-Raf kinase represents an excellent target for anticancertherapy based on preclinical target validation, epidemiology anddrugability. Small molecule inhibitors of B-Raf are being developed foranticancer therapy. Examples of small molecule inhibitors of B-Rafinclude but are not limited to dabrafenib (Tafinlar®). Nexavar®(sorafenib tosylate) is a multikinase inhibitor, which includesinhibition of B-Raf, and is approved for the treatment of patients withadvanced renal cell carcinoma and unresectable hepatocellular carcinoma.Other Raf inhibitors have also been disclosed or have entered clinicaltrials, for example GSK-2118436, RAF-265, vemurafenib (Zelboraf,PLX-4032), PLX3603 and XL-281. Examples of small molecule inhibitors ofMEK include but are not limited to trametinib (Mekinist®), Other MEKinhibitors include ARRY-886 (AZD6244);

29) Cell cycle signaling inhibitors, including inhibitors of cyclindependent kinases (CDKs) are also useful in combination with thecompounds of the invention in the compositions and methods describedabove. Examples of cyclin dependent kinases, including CDK2, CDK4, andCDK6 and inhibitors for the same are described in, for instance, RosaniaG. R. et al., Exp. Opin. Ther. Patents (2000) 10 215-230;

30) Inhibitors of phosphatidyl inositoi-3-0H kinase family membersincluding blockers of Pl3-kinase, ATM, DNA-PK, and Ku may also be usefulin combination with the present invention;

31) Antagonists of smoothened receptor (SMO) may also be useful incombination with the present invention. Examples of antagonists ofsmoothened receptor include but are not limited to vismodegib(Erivedge®);

32) Inhibitors of protein translation may also be useful in combinationwith the present invention. Examples of inhibitors of proteintranslation include but are not limited to omacetaxine mepesuccinate(Synribo®); and

33) anti-cancer agents with other mechanisms of action includingmiltefosine (Impavido and Miltex), masoprocol, mitoguazone,alitretinoin, mitotane, arsenic trioxide, celecoxib, and anagrelide.

Compounds disclosed herein may also be employed in conjunction withanti-emetic agents to treat nausea or emesis, including acute, delayed,late-phase, and anticipatory emesis, which may result from the use of acompound as disclosed herein, alone or with radiation therapy. For theprevention or treatment of emesis, a compound as disclosed herein may beused in conjunction with other anti-emetic agents, especiallyneurokinin-1 receptor antagonists, 5HT3 receptor antagonists, such asondansetron, granisetron, tropisetron, and zatisetron, GABAB receptoragonists, such as baclofen, a corticosteroid such as Decadron(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten orothers such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401,3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, anantidopaminergic, such as the phenothiazines (for exampleprochlorperazine, fluphenazine, thioridazine and mesoridazine),metoclopramide or dronabinol. In another embodiment, conjunctive therapywith an anti-emesis agent selected from a neurokinin-1 receptorantagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosedfor the treatment or prevention of emesis that may result uponadministration of the instant compounds.

A compound as disclosed herein may also be administered with an agentuseful in the treatment of anemia. Such an anemia treatment agent is,for example, a continuous eythropoiesis receptor activator (such asepoetin alfa).

A compound as disclosed herein may also be administered with an agentuseful in the treatment of neutropenia. Such a neutropenia treatmentagent is, for example, a hematopoietic growth factor which regulates theproduction and function of neutrophils such as a human granulocytecolony stimulating factor, (G-CSF). Examples of a G-CSF includefilgrastim.

A compound as disclosed herein may also be useful for treating orpreventing cancer in combination with siRNA therapeutics.

A compound as disclosed herein may also be useful for treating cancer incombination with the following therapeutic agents: abarelix (PlenaxisDepot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb(Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®);altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®);arsenic trioxide (Trisenox®); asparaginase (Elspar®); Axitinib(Inlyta®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotenecapsules (Targretin®); bexarotene gel (Targretin®); bicalutamide(Casodex®), bleomycin (Blenoxane®); bortezomib (Velcade®); busulfanintravenous (Busulfex®); busulfan oral (Myleran®); calusterone(Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®);carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine withPolifeprosan 20 Implant (Gliadel Wafer®); celecoxib (Celebrex®);cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®);cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide(Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®);cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); cytarabineliposomal (DepoCyt®); dacarbazine (DTIC-Dome®); dactinomycin,actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); dasatinib(Sprycel®); daunorubicin liposomal (DanuoXome®); daunorubicin,daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®);Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel(Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®,Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal(Doxil®); doxorubicin liposomal (Doxil®); dromostanolone propionate(Dromostanolone®); dromostanolone propionate (Masterone Injection®);Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®);Epoetin alfa (Epogen®); erlotinib (Tarceva®); estramustine (Emcyt®);etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®);exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine(intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU(Adrucil®); flutamide (Eulexin®), fulvestrant (Faslodex®); gefitinib(Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®);goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®);histrelin acetate (Histrelin Implant®); hydroxyurea (Hydrea®);Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide(IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®);Interferon alfa-2b (Intron A®); ipilimumab (Yervoy®), irinotecan(Camptosar®); lapatinib (TYKERB®), lenalidomide (Revlimid®); letrozole(Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate(Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®);meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate(Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP(Purinethol®); mesna (Mesnex®); mesna (Mesnex Tabs®); methotrexate(Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®);mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolonephenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab(Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel(Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles(Abraxane®); palifermin (Kepivance®); panitumumab (VECTIBIX®),pamidronate (Aredia®); Pazopanib (Votrient®), pegademase (Adagen(Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim(Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);pertuzumab (OMNITARG®, 2C4), pipobroman (Vercyte®); plicamycin,mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine(Matulane®); quinacrine (Atabrine®); Rapamycin (Sirolimus, RAPAMUNE®,),Rasburicase (Elitek®); Rituximab (Rituxan®); rubitecan (Orathecin),ruxolitinib (Jakafi®); sargramostim (Leukine®); Sargramostim (Prokine®);sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate(Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide(Temodar®); temsirolimus (Torisel®); teniposide, VM-26 (Vumon®);testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa(Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab(Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab(Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (UracilMustard Capsules®); valrubicin (Valstar®); vandetanib (ZACTIMA®),vemurafenib (Zelboraf®), vinblastine (Velban®); vincristine (Oncovin®);vinorelbine (Navelbine®); vorinostat (Zolinza®); zoledronate (Zometa®),nilotinib (Tasigna®); and dasatinib (Sprycel®). ARRY-886 (Mek inhibitor,AZD6244), SF-1126 (PI3K inhibitor,), BEZ-235 (PI3K inhibitor), XL-147(PI3K inhibitor), PTK787/ZK 222584, crizotinib (Xalkori®), andvemurafenib (Zelboraf®).

In any case, the multiple therapeutic agents (at least one of which is acompound disclosed herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes tofour weeks.

Thus, in another aspect, certain embodiments provide methods fortreating disorders and symptoms relating cancer in a human or animalsubject in need of such treatment comprising administering to saidsubject an amount of a compound disclosed herein effective to reduce orprevent said disorder in the subject, in combination with at least oneadditional agent for the treatment of said disorder that is known in theart. In a related aspect, certain embodiments provide therapeuticcompositions comprising at least one compound disclosed herein incombination with one or more additional agents for the treatment ofdisorders and symptoms relating to cancer.

The compounds, compositions, and methods disclosed herein are useful forthe treatment of disease. In certain embodiments, the diseases is one ofdysregulated cellular proliferation, including cancer. The cancer may behormone-dependent or hormone-resistant, such as in the case of breastcancers. In certain embodiments, the cancer is a solid tumor. In otherembodiments, the cancer is a lymphoma or leukemia. In certainembodiments, the cancer is and a drug resistant phenotype of a cancerdisclosed herein or known in the art. Tumor invasion, tumor growth,tumor metastasis, and angiogenesis may also be treated using thecompositions and methods disclosed herein. Precancerous neoplasias arealso treated using the compositions and methods disclosed herein.

Cancers to be treated by the methods disclosed herein include coloncancer, breast cancer, ovarian cancer, lung cancer and prostrate cancer;cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx,pharynx), esophagus, stomach, small intestine, large intestine, colon,rectum, liver and biliary passages; pancreas, bone, connective tissue,skin, cervix, uterus, corpus endometrium, testis, bladder, kidney andother urinary tissues, including renal cell carcinoma (RCC); cancers ofthe eye, brain, spinal cord, and other components of the central andperipheral nervous systems, as well as associated structures such as themeninges; and thyroid and other endocrine glands. The term “cancer” alsoencompasses cancers that do not necessarily form solid tumors, includingHodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma andhematopoietic malignancies including leukemias (Chronic LymphocyticLeukemia (CLL), Acute Lymphocytic Leukemia (ALL)) and lymphomasincluding lymphocytic, granulocytic and monocytic. Additional types ofcancers which may be treated using the compounds and methods of theinvention include, but are not limited to, adrenocarcinoma,angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma,basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma,chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma,endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor,epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tractcancers, glioblastoma multiforme, head and neck cancer,hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi's sarcoma,large cell carcinoma, leiomyosarcoma, leukemias, liposarcoma, lymphaticsystem cancer, lymphomas, lymphangiosarcoma,lymphangioendotheliosarcoma, medullary thyroid carcinoma,medulloblastoma, meningioma mesothelioma, myelomas, myxosarcomaneuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma,epithelial ovarian cancer, papillary carcinoma, papillaryadenocarcinomas, paraganglioma, parathyroid tumours, pheochromocytoma,pinealoma, plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceousgland carcinoma, seminoma, skin cancers, melanoma, small cell lungcarcinoma, non-small cell lung carcinoma, squamous cell carcinoma, sweatgland carcinoma, synovioma, thyroid cancer, uveal melanoma, and Wilm'stumor.

In certain embodiments, the compositions and methods disclosed hereinare useful for preventing or reducing tumor invasion and tumormetastasis.

In certain embodiments, the compositions and methods disclosed hereinare useful for preventing or reducing angiogenesis and disorders relatedto angiogenesis. Besides being useful for human treatment, certaincompounds and formulations disclosed herein may also be useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. More preferredanimals include horses, dogs, and cats.

LIST OF ABBREVIATIONS

CHCl₃=chloroform; i-PrOH=isopropanol; H₂O=water; DCM=dichloromethane;Na₂SO₄=sodium sulfate; MgSO₄=magnesium sulfate; EtOAc=ethyl acetate;EtOH=ethanol; Et₂O=diethyl ether; THF=tetrahydrofuran;NMP=N-Methyl-2-pyrrolidone; NaOH=sodium hydroxide; MeOH=methanol;CDCl₃=deuterated chloroform; HCl=hydrochloric acid; MeCN=acetonitrile;Cs₂CO₃=cesium carbonate; DMF=N,N-dimethylformamide; CD₃OD=deuteratedmethanol; DMSO-d₆=deuterated dimethyl sulfoxide; DMSO=dimethylsulfoxide; TFA=trifluoroacetic acid; AcOH=acetic acid; HBr=hydrobromicacid; HCOOH=formic acid; K₂CO₃=potassium carbonate;DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; NaHCO₃=sodium hydrogencarbonate; KCN=potassium cyanide; TEA=Et₃N=triethylamine;DMAP=4-dimethylaminopyridine; NH₂OH.HCl=hydroxylammonium chloride;DIEA=N,N-diisopropylethylamine; LiOH=lithium hydroxide; NH₄HCO₃=ammoniumhydrogen carbonate; NH₄OH=ammonium hydroxide; K₃PO₄=potassium phosphatetribasic; NaOtBu=sodium t-butoxide; CuBr₂=copper (II) bromide;CuCl₂=copper (II) chloride; CuCN(LiCl)₂=Copper(I) cyanide di(lithiumchloride) complex; EDC.HCl=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride; HOBT=1-hydroxybenzotriazole;PyBop=(Benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate; LiCl=lithium chloride; NaI=sodium iodide;NaBr=sodium bromide; N₂=nitrogen; Ar=argon; MnO₂=manganese dioxide;HATU=2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium; BH₃-THF=borane tetrahydrofurancomplex solution; POCl₃=phosphorus oxychloride; Ac₂O=acetic anhydride;NH₂NH₂.H₂O=hydrazine hydrate; NaBH₄=sodium borohydride; NaBH₃CN=sodiumcyanoborohydride; n-BuLi=n-butyllithium; CH₃I=methyl iodide; CS₂=carbondisulfide; AIBN=azobisisobutyronitrile; KF=potassium fluoride;Bu₃SnH=tributyltin hydride;RuPhos=2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl;XPhos=2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; andPd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0);Pd(Ph₃)₄=tetrakis(triphenylphosphine)palladium(0);NCS=N-chlorosuccinimide; DEAD=diethyl azodicarboxylate; OsO₄=osmiumtetraoxide; DIBAL-H=di-iso-butyl aluminium hydride; t-BuOH=tert-butanol;Py=pyridine; NaOMe=sodium methoxide; prep-HPLC=preparativehigh-performance liquid chromatography.

General Methods for Preparing Compounds

The following schemes can be used to practice the present invention.Additional structural groups, including but not limited to those definedelsewhere in the specification and not shown in the compounds describedin the schemes can incorporated to give various compounds disclosedherein, or intermediate compounds which can, after further manipulationusing techniques known in the art, be converted to compounds of thepresent invention. For example, in ceratin embodiments the A, B, D, andE rings in the structures described in the schemes can be substitutedwith various groups as defined herein.

One route for preparation of compounds of the present invention isdepicted in Scheme 1. Ethyl 2-chloro-2-oxoacetate can be condensed witha hydroxyamidine, and cyclized in refluxing pyridine to form a1,2,4-oxadiazole. The resulting ester can be treated with hydrazinehydrate in refluxing ethanol to give the corresponding hydrazide. Thiscan in turn be condensed with a substituted amidine in refluxing solventsuch as THF to yield an intermediate, which after a solvent switch toethane-1,2-diol and refluxing the reaction for several hours the desired1,2,4-triazole can be prepared. Alternatively, the hydrazide can bemixed with the amidine hydrochloride salt in the presence of a base suchas sodium hydroxide in a solvent such as xylene and the mixture stirredat 170° C. for 36 h to yield the 1,2,4-triazole directly. Alkylation ofthe triazole with an appropriately substituted benzyl halide, orheterocyclic methyl halide, or equivalent synthon yields a mixture ofregioisomers. This transformation can be achieved using reagents suchCs₂CO₃ or K₂CO₃ in a polar solvent like DMF or DMSO, or K₂CO₃ in thepresence of NaI in THF. These transformations can be accomplished at RT,although with some substrates it may be necessary to use elevatedtemperatures and/or microwave irradiation to drive the reaction tocompletion. The regioisomer can be separated at this stage, or later inthe synthetic sequence by chromographic methods such as columnchromatography or HPLC to yield compounds of this invention.

In a related manner, other heterocyclic carboxylic acids can betransformed to the corresponding hydrazide, for instance as depicted inScheme 2 by coupling with Boc hydrazide, using a coupling reagent suchas HATU in the presence of a base like K₂CO₃ in a solvent like DCM.Thereafter the Boc group can be removed using acid such as TFA in asolvent such as DCM. The resulting hydrazides can be coupled asdescribed above with a substituted amidine to yield the corresponding1,2,4-triazole, and alkylated as described in Scheme 1 above to yieldthe desired compound of this invention. These compounds can be furthermanipulated synthetically as described hereafter.

Compounds of the invention bearing 2-halopyridines, such as2-chloropyridine, or heterocycles bearing a similarly reactive halogensubstituents, for instance 2-chloropyrimidines or 2-chlorothiazoles, canbe displaced with a variety of nucleophiles, such as primary andsecondary amines [Scheme 3]. For example, by refluxing an excess of theamine at 120° C. overnight, using a solvent such as DMSO if required.

Alternatively, these heterocyclic halides or aromatic halides can becross coupled with amines using palladium catalysis, using methods knownto those trained in the art [Scheme 4]. For example, aromatic bromidescan be coupled using a catalyst system comprising ofdicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine andchloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) in the presence of a base suchas NaOtBu in THF at 65° C. for 2 h. Alternatively, a catalyst systemcomprising of X-Phos, Pd₂(dba)₃ and N′,N′-dimethylethane-1,2-diamine inthe presence of a base such as Cs₂CO₃ and be used for the transformationin a solvent such as dioxane. The reaction being conducted by microwaveirradiation at 120° C. for 1 h. In addition, this transformation can beconducted using a catalytic system comprising of X-Phos and Pd₂(dba)₃ inthe presence of a base such as Cs₂CO₃ in a solvent such as toluene, byheating at 140° C. for 18 h.

Furthermore, these heterocyclic halides or aromatic halides can be crosscoupled with stannanes or boronates using palladium catalysis, applyingmethods known to those trained in the art [Scheme 5]. For example,aromatic bromides can be coupled with alkenyl stannanes using a catalystsystem comprising of tetrakis(triphenylphosphine)palladium(0) in thepresence of a base such as K₂CO₃ in a solvent such as dioxane,conducting the reaction thermally at 110° C. for 12 h.

Compounds of the present invention can be further manipulated usingsynthetic transformation known to those trained in the art to yieldalternative compounds also covered within the scope of this invention.For instance, as is depicted in Scheme 6, compounds bearing a protectedamine can be deprotected using synthetic transformations known to thosetrained in the art, for example a Cbz-protecting group can be removedusing HBr in AcOH/H₂O at temperatures around 40° C. The resultingprimary or secondary amine can undergo a reductive amination reaction toyield higher substituted amines, for instance by reacting the amine withan aldehyde in the presence of a reducing agent such as NaBH₃(CN) in aalcoholic solvent.

Alternatively, compounds of the present invention containing a primaryor a secondary amine can be further manipulated by reaction with acarboxylic acid in the presence of coupling agents like EDCI or HATU, acarboxylic acid chloride, or a sulfonyl chloride in the presence of abase such as triethylamine in a suitable solvent, for example DCM, asdepicted in Scheme 7.

Another route for the preparation of compounds of the present inventionis depicted in Scheme 8. Starting from compounds of the inventionbearing a carboxylic ester, these can readily be transformed intoamides. For example, a mixture of the ester can be reacted with thedesired amine in the presence of 1,2,4-triazole and DBU, and heated to70-100° C. overnight.

Compounds of the invention bearing a phenol moiety can be furthermanipulated by reaction with a variety of alkylating reagents such asalkyl-, benzyl- or allyl-halides, in the presence of a base such asK₂CO₃ or CsCO₃ in a suitable solvent like DMF, occasionally heating thereaction if necessary [Scheme 9a]. In addition, if such transformationsare carried out with compounds of the invention bearing2-hydroxypyridines, the products of N-alkylation can be obtained as wellas the products of O-alkylation. An additional way to functionalize thecompounds of this invention bearing a phenol moiety is described inScheme 9b, and consists in reacting a suitable alcohol in the presenceof an azodicarboxylate reagent, like diethyl azodicarboxylate (DEAD) anda phosphine, for example Ph₃P, according to the methodology described byMistunobu et al. (Synthesis 1981, 1-28) or any modification thereofknown to those trained in the art.

An additional route to prepare the compounds of this invention isdescribed in Scheme 10. Compounds bearing an alkenyl group can befurther manipulated by oxidative transformations. For example, they canundergo di-hydroxylation by applying methods known to those trained inthe art, including using a catalytic amount of OsO₄ in the presence ofN-methylmorpholine-oxide in a suitable solvent such as tet-butanol.Alternatively, the double bond can be converted into the correspondingepoxide by a suitable oxidizing reagent, for example3-chloro-benzoperoxy acid, and the epoxide species could in turn befurther functionalized by reaction with a suitable nucleophilic reagentsuch an amine [Scheme 10].

Furthermore, compounds described in this invention bearing anunsubstituted aniline group can be further manipulated by methods knownto those skilled in the art and converted into compounds bearing asulfonamide moiety, as depicted in Scheme 11. For example, treatment ofunsubstituted anilines with sodium nitrite in the presence of suitableacidifing reagents, such as acetic acid and hydrochloric acid, followedby treatment with sulfur dioxide in the presence of a suitable inorganicsalt such as CuCl₂, results in the formation of the correspondingsulfonyl chloride. The latter could then be further progressed to asulfonamide by reaction with an amine in the presence of a base such aspyridine, in a suitable solvent, for example DCM.

Another route for the preparation of compounds of the present inventionis depicted in Scheme 12, where in 1,3,4-oxadiazoles can be preparedusing synthetic procedures known to those trained in the art. Startingfrom a suitable triazole carboxylic acid ester, this can be alkylated togive the desired substituted benzyl triazole, or heteromethyltriazole.This synthetic sequence may give regioisomers which can be separated atvarious points along the synthetic sequence using chromaographicaltechniques. In turn, the resulting ester product is reacted withhydrazine hydrate in an alcoholic solvent to give the correspondinghydrazide. This can be coupled with an appropriately substituted benzoicor heterocyclic acid using reagents such as phosphorous oxychloride atelevated temperatures to synthesize the desired 1,3,4-oxadiazoles ofthis invention. As described above these can be transformed into othercompounds described in this invention using protocols described aboveand below.

Another route for the preparation of compounds of the present inventionis depicted in Scheme 13 for targeting isomeric oxadiazoles. Substitutedtriazole esters are converted to the corresponding primary amides, forinstance by using methanolic ammonia solution at elevated temperature.These amides are alkylated with suitable functionalized alkyl halidesand tosylates, for example using a base such as Cs₂CO₃ or K₂CO₃ in asolvent such as DMF or THF to yield isomeric N-substituted triazoleswhich can be separated using chromographic techniques such as columnchromatography on silica. The primary amide can then be dehydrated tothe corresponding nitrile, for example by using trifluoroaceticanhydride and triethylamine in a solvent such as DCM or other methodsknown to those trained in the art. Fictionalization on the periphery ofthe molecule can then be undertaken if required using methods describedabove and below. The nitrile can then be transformed into thehydroxyamidine through treatment with hydroxylamine hydrochloride in thepresence of a tertiary amine base, in a alcohol solvent at elevatedtemperature. Coupling with a carboxylic acids, using coupling reagentssuch as carbonyl diimidazole in a solvent like DCM leads to acyclization precursor which can be dehydrated to compounds of thisinvention at elevated temperature, such as heating at 135° C. in asolvent like DMF.

Compounds described in this invention containing a thiazole ring can beprepared by those skilled in the art according to a synthetic route likethe one described in Scheme 14. A suitable alpha-bromo acetophenone canbe converted to a thiazole 2-carboxylate by reaction with anamino-2-thioxoacetate heating at reflux in a solvent such as EtOH. Thethiazole 2-carboxylate can then be progressed to the correspondinghydrazide by stirring in a suitable solvent, such as MeOH, in thepresence of hydrazine hydrate. Reaction with a suitable amidine followedby thermal cyclization, for example in a high boiling solvent such asethylene glycol, can be used to access a thiazole-containing tricyclicintermediate. The latter can in turn be alkylated as previouslydescribed in Scheme 1, and substituent A could be further manipulated asdescribed in Schemes 3 to 11.

Additionally, compounds described in this invention containing anoxazole ring can be prepared by those skilled in the art according to asynthetic route like the one described in Scheme 15. A suitablealpha-amino acetophenone can be acylated with a 2-chloro-2-oxo-acetatein the presence of a base such as triethylamine in a solvent such asincluding DCM, NMP, MeCN. The resulting alpha-ketoamide product can thenbe cyclized to the corresponding oxazole-2-carboxylate by heating in thepresence of a condensing agent such as POCl₃, and the resulting productcan in turn be converted to the carbohydrazide by stirring in a solventsuch as MeOH or EtOH in the presence of hydrazine hydrate. In analogousmanner to the synthetic route previously described in Scheme 14,reaction with a suitable amidine followed by condensation in a solventsuch as ethylene glycol or THF affords the desired oxazole-containingtricyclic intermediate. The latter can in turn be alkylated aspreviously described in Scheme 1, and substituent A could be furthermanipulated as described in Schemes 3 to 11.

Compounds described in the present invention that contain an isoxazolering can be prepared in a regiospecific manner by synthetic routes suchthose described in Scheme 16. In one case (Scheme 16a) a suitablebenzaldehyde can be converted in the corresponding chloro-oxime bycondensation with hydroxalamine in a solvent such as MeOH at elevatedtemperature, followed by treatment with a suitable chlorinating agent,for example N-chlorosuccinimide, in a solvent such as DMF. Thermalcycloaddition with methylpropiolate in the presence of a suitable base,for example triethylamine, in a solvent such as toluene gives theisoxazole-5-carboxylate intermediates. Functional group manipulationssimilar to those described in Schemes 14 and 15 can be used to progressthe latter intermediates to the fully functionalized isoxazolederivatives described here in, and substituent A could be furthermanipulated as described in Schemes 3 to 11. In a similar fashion,isoxazole-3-carboxylate intermediates can be prepared by condensation ofa suitable acetophenone with an oxalate in the presence of a strongbase, such as NaOMe in MeOH, followed by cyclization of the deriveddiketo ester in the presence of hydroxylamine [Scheme 16b]. Functionalgroup manipulations previously described in Schemes 14 and 15 can thenbe employed to access the fully functionalized isomeric isoxazoleintermediates, substituent A could be further manipulated as describedin Schemes 3 to 11.

The invention is further illustrated by the following examples, whichmay be made my methods known in the art and/or as shown below.Additionally, these compounds may be commercially available.

Intermediate A Ethyl3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate

Step 1

To a solution of (E)-N′-hydroxy-4-(trifluoromethoxy)benzimidamide (3.0g, 13.6 mmol) and pyridine (1.6 g, 20.4 mmol) in CHCl₃ (20 mL), ethyl2-chloro-2-oxoacetate (2.2 g, 16.4 mmol) was added slowly at 0° C. Themixture was stirred at reflux for 3 h, and then concentrated to give thecrude product, which was purified by silica gel column chromatography(Petroleum ether:EtOAc=10:1) to give ethyl3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate as a whitesolid (4.5 g, 82%). MS (ES+) C₁₂H₉F₃N₂O₄ requires: 302. found:303[M+H]⁺.

Intermediate B5-(5-Methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

Step 1

3-(4-(Trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide

To the solution of ethyl3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (13.6 g,45.0 mmol) in EtOH (200 mL), NH₂NH₂.H₂O (80%, 14 mL, 225 mmol) wasadded. The reaction mixture was stirred at RT overnight. The desiredcompound precipitated from the reaction mixture, filtered and washedwith EtOH (50 mL) to afford3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide as alight yellow solid (9.7 g, 75%). MS (ES+) C₁₀H₇F₃N₄O₃ requires: 288.found: 289 [M+H]⁺.

Step 2

5-(5-Methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

To a solution of3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide (9.7 g,33.7 mmol) and acetimidamide hydrochloride (4.8 g, 50.5 mmol) in dry THF(300 mL), NaOH (2.0 g, 50.5 mmol) was added at RT. The mixture wasrefluxed overnight. The solution was cooled, concentrated andethane-1,2-diol (100 mL) was added. The resulting mixture was heated at180° C. for 3 h, cooled to RT, diluted with H₂O (800 mL), and extractedwith EtOAc (3×400 mL). The combined organic layers were washed with H₂O(300 mL) and brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford the crude solid product,which was treated with EtOAc (150 mL). The resulting suspension wasstirred at RT for 15 min, and then filtered to afford 4.8 g of the puredesired compound. The remaining filtrate was concentrated and purifiedby silica gel column chromatography (Petroleum ether:EtOAc=1:1) toafford 1.4 g of another batch of5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazoleas a white solid-overall 6.2 g, yield 59%. MS (ES+) C₁₂H₈F₃N₅O₂requires: 311. found: 312 [M+H]⁺.

The invention is further illustrated by the following examples, whichmay be made my methods known in the art and/or as shown below.Additionally, these compounds may be commercially available.

EXAMPLE 14-(4-((5-Methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazin-1-iumtrifluoroacetate

Step 1

5-(5-Methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

To a solution of N′-hydroxy-4-(trifluoromethoxy)benzimidamide (1.3 g,5.1 mmol) and 5-methyl-1H-1,2,4-triazole-3-carboxylic acid (650 mg, 5.1mmol) in DMF (15 mL), EDC.HCl (980 mg, 5.1 mmol) and HOBT (690 mg, 5.1mmol) were added at RT. The mixture was stirred at RT for 1 h, and thenheated to 140° C. for 3 h. The resulting mixture was cooled, dilutedwith H₂O (20 mL) and extracted with EtOAc (4×40 mL). The combinedorganic layers were washed with H₂O (10 mL) and brine (10 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure, and theresidue was purified by Combiflash reverse phase chromatography (50%˜60%MeCN/H₂O containing 0.01% trifluoroacetic acid) to give5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazoleas a white solid (590 mg, 37%). MS (ES+) C₁₂H₈F₃N₅O₂ requires: 311.found: 312[M+H]⁺.

Step 2

Benzyl4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate

To a solution of5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole(311 mg, 1.0 mmol) and benzyl4-(4-(chloromethyl)pyridin-2-yl)piperazine-1-carboxylate (690 mg, 2.0mmol) in DMF (15 mL), Cs₂CO₃ (820 mg, 2.5 mmol) was added at RT. Themixture was stirred at RT overnight, then diluted with H₂O (50 mL), andextracted with EtOAc (3×50 mL). The combined organic layers were washedwith H₂O (20 mL) and brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (Petroleum ether:EtOAc=1:2) to givebenzyl4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate(350 mg, 56%) as a yellow oil and benzyl4-(4-((3-methyl-5-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine-1-carboxylateas a white solid (50 mg, 8%). MS (ES+) C₃₀H₂₇F₃N₈O₄ requires: 620.found: 621[M+H]⁺.

Step 3

4-(4-((5-Methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazin-1-iumtrifluoroacetate

To a solution of benzyl4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate(200 mg, 0.30 mmol) in AcOH (1 mL), HBr (2 mL, 48% in H₂O) was added atRT. The mixture was stirred at 40° C. for 1 h, and then concentratedunder reduced pressure to give the crude product, which was purified byprep-HPLC (Mobile phase: A=0.01% TFA/H₂O, B=MeCN; Gradient: B=60%-95% in18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to afford4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazin-1-ium2,2,2-trifluoroacetate as a white solid (130 mg, 84%). MS (ES+)C₂₂H₂₁F₃N₈O₂ requires: 486. found: 487 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆)δ 8.98 (s, 2H), 8.22 (d, J=8.5 Hz, 2H), 8.15 (d, J=5.0 Hz, 1H), 7.61 (d,J=8.5 Hz, 2H), 6.87 (s, 1H), 6.57 (d, J=5.0 Hz, 1H), 5.54 (s, 2H),3.73-3.71 (m, 4H), 3.22-3.19 (m, 4H), 2.59 (s, 3H).

EXAMPLE 25-(5-Methyl-1-((2-(4-methylpiperazin-1-yl)pyridin-4-yl)methyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

Step 1

5-(5-Methyl-1-((2-(4-methylpiperazin-1-yl)pyridin-4-yl)methyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

The mixture of4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazin-1-iumtrifluoroacetate (100 mg, 0.2 mmol), formaldehyde (0.5 mL, 6.0 mmol, 38%in H₂O) and paraformaldehyde (100 mg, 3.3 mmol) in EtOH (1 mL) wasstirred at RT, then treated with NaBH₃CN (63 mg, 1.0 mmol) in oneportion. The mixture was stirred at RT for 3 h, and then concentratedunder reduced pressure to give the crude product, which was purified bypre-HPLC (Mobile phase: A=10 mM NH₄HCO₃/H₂O, B=MeCN; Gradient: B=60%-95%in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to afford5-(5-methyl-1-((2-(4-methylpiperazin-1-yl)pyridin-4-yl)methyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazoleas a white solid (45 mg, 45%). MS (ES+) C₂₃H₂₃F₃N₈O₂ requires: 500.found: 501 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 8.22 (d, J=8.3 Hz, 2H),8.08 (d, J=5.3 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 6.77 (s, 1H), 6.42 (d,J=5.3 Hz, 1H), 5.50 (s, 2H), 3.50-3.48 (m, 4H), 2.58 (s, 3H), 2.41-2.32(m, 4H), 2.20 (s, 3H).

EXAMPLE 31-Methyl-4-(4-((5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine

Step 1

tert-Butyl 2-(5-phenylfuran-2-carbonyl)hydrazinecarboxylate

To a stirred suspension of 5-phenylfuran-2-carboxylic acid (200 mg, 1.06mmol), tert-butyl hydrazinecarboxylate (140 mg, 1.06 mmol) and K₂CO₃(440 mg, 3.19 mmol) in DCM (20 mL), HATU (404 mg, 1.06 mmol) was added.The mixture was stirred at RT for 3 h, then filtered to give the crudetert-butyl 2-(5-phenylfuran-2-carbonyl)hydrazinecarboxylate as a whitesolid (300 mg, 93%), which was directly used for next step withoutfurther purification. MS (ES+) C₁₆H₁₈N₂O₄ requires: 302. found: 247[M+H−56]⁺.

Step 2

5-Phenylfuran-2-carbohydrazide

To a solution of tert-butyl2-(5-phenylfuran-2-carbonyl)hydrazinecarboxylate (300 mg, 1 mmol) in DCM(10 mL), TFA (4.85 g, 50 mmol) was added dropwise. The mixture wasstirred at RT overnight, then concentrated under reduced pressure andpurified by silica gel column chromatography (EtOAc:Petroleumether:TEA=50:50:1) to afford 5-phenylfuran-2-carbohydrazide as a lightyellow solid (150 mg, 74%). MS (ES+) C₁₁H₁₀N₂O₂ requires: 202. found:203 [M+H]⁺.

Step 3

5-Methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazole

To a suspension of 5-phenylfuran-2-carbohydrazide (100 mg, 0.5 mmol) andacetamidine hydrochloride (141 mg, 1.49 mmol) in THF (20 mL), NaOH (59mg, 1.49 mmol) was added. The mixture was refluxed overnight, cooled,then treated with H₂O (30 ml) and extracted with EtOAc (3×20 mL). Thecombined organic layers were washed with H₂O (1×10 mL) and brine (1×10mL), dried over Na₂SO₄, filtered, concentrated under reduced pressureand purified by silica gel column chromatography (EtOAc:Petroleumether=1:1) to afford 5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazoleas a white solid (15 mg, 13%). MS (ES+) C₁₃H₁₁N₃O requires: 225. found:226 [M+H]⁺.

Step 4

2-Chloro-4-((5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridineand 2-chloro-4-((3-methyl-5-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridine

To a solution of 5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazole (15mg, 0.07 mmol) and 2-chloro-4-(chloromethyl)pyridine (13 mg, 0.08 mmol)in DMF (5 mL), Cs₂CO₃ (33 mg, 0.1 mmol) was added. The mixture wasstirred at RT overnight, then treated with H₂O (30 mL), and extractedwith EtOAc (3×30 mL). The combined organic layers were washed with H₂O(1×10 mL) and brine (1×10 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford the crude product, whichwas purified by silica gel column chromatography (EtOAc:Petroleumether=100:20) to give the mixture of2-chloro-4-((5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridineand2-chloro-4-((3-methyl-5-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridineas a yellow solid (10 mg, 42%). MS (ES+) C₁₉H₅ClN₄O requires: 350.found: 351 [M+H]⁺.

Step 5

1-Methyl-4-(4-((5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine

A mixture of2-chloro-4-((5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridine and2-chloro-4-((3-methyl-5-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridine(100 mg, 0.3 mmol) was treated with 1-methylpiperazine (280 mg, 3 mmol)in DIEA (10 ml), and refluxed overnight. The mixture was cooled,concentrated, treated with H₂O (30 mL) and extracted with EtOAc (3×30mL). The combined organic layers were washed with H₂O (1×10 mL) andbrine (1×10 mL), dried over Na₂SO₄, filtered, and concentrated to affordthe crude product, which was purified by prep-HPLC (Mobile phase: A=0.1%NH₄OH/H₂O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge (C18,5 um, 30 mm×150 mm) to give1-methyl-4-(4-((5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazineas a yellow solid (66 mg, 53%) and1-methyl-4-(4-((3-methyl-5-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazineas a yellow solid (42 mg, 34%). For1-methyl-4-(4-((5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine:MS (ES+) C₂₄H₂₆N₆O requires: 414. found: 415 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.14 (d, J=5.1 Hz, 1H), 7.89-7.72 (m, 2H), 7.39 (t, J=7.8 Hz,2H), 7.28 (td, J=7.4, 1.3 Hz, 1H), 7.04 (d, J=3.5 Hz, 1H), 6.76 (d,J=3.5 Hz, 1H), 6.44-6.26 (m, 2H), 5.26 (s, 2H), 3.53 (t, J=5.0 Hz, 4H),2.48 (t, J=5.1 Hz, 4H), 2.44 (s, 3H), 2.32 (s, 3H).

For1-methyl-4-(4-((3-methyl-5-(5-phenylfuran-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine:MS (ES+) C₂₄H₂₆N₆O requires: 414. found: 415 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.12 (d, J=5.1 Hz, 1H), 7.63-7.55 (m, 2H), 7.38 (t, J=7.6 Hz,2H), 7.30 (dd, J=14.4, 6.9 Hz, 1H), 7.11 (d, J=3.5 Hz, 1H), 6.77 (d,J=3.6 Hz, 1H), 6.51-6.40 (m, 2H), 5.60 (s, 2H), 3.46 (t, J=5.1 Hz, 4H),2.45 (s, 3H), 2.43 (t, J=5.1 Hz, 4H), 2.30 (s, 3H).

EXAMPLE 43-(1-Benzyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-5-yl)pyridin-1-iumtrifluoroacetate

Step 1

N′-benzyl-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide

To a suspension of ethyl3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate(Intermediate A) (1.0 g, 3.3 mmol) and K₂CO₃ (1.1 g, 13 mmol) in THF (17mL) was added benzylhydrazine dihydrochloride (780 mg, 5.0 mmol). Themixture was heated to 70° C. for 3 h. The mixture was cooled to RT,filtered (Celite), and concentrated under reduced pressure. The crudeoil was purified by Biotage (5% EtOAc/Hexane-60% EtOAc) to provide awhite solid (500 mg, 40%): MS (ES+) C₁₇H₁₃F₃N₄₀₃ requires: 378. found:379 [M+H]+.

Step 2

3-(1-Benzyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-5-yl)pyridin-1-iumtrifluoroacetate

A mixture ofN′-benzyl-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide(40 mg, 0.11 mmol) and nicotinimidamide hydrochloride (33 mg, 0.21 mmol)in 2N NaOH ethanol solution (1.1 mL, 0.21 mmol) was heated to 65° C. for30 min. The mixture was cooled to RT and concentrated under reducedpressure. The crude mixture was taken up in NMP (0.5 mL) and heated to140° C. for 2 h. The mixture was cooled to RT and partitioned betweenH₂O (0.5 mL) and EtOAc (0.5 mL). The aqueous layer was extracted withEtOAc (3×0.5 mL). The combined organic layers were washed with H₂O(3×0.5 mL) and brine (0.5 mL), dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The crude oil was purified by reverse-phase HPLCto provide the TFA salt as a white solid (1.8 mg, 3%):¹H NMR (600 MHz,CDCl₃) δ ppm 8.93 (s, 1H), 8.79 (d, J=4.8 Hz, 1H), 8.29 (d, J=8.1 Hz,2H), 8.08 (d, J=8.0 Hz, 1H), 7.52 (app. dd, J=7.5 Hz, 5.5 Hz, 1H),7.37-7.30 (m, 5H), 7.20 (d, J=7.3 Hz, 2H), 5.62 (s, 2H); MS (ES+)C₂₃H₁₅F₃N₆O₂ requires: 464. found: 465 [M+H]+.

EXAMPLE 52-(4,4-Dimethylpiperidin-1-yl)-4-((5-methyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-1-iumtrifluoroacetate

Step 1

2-(5-Methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole

To a solution of 5-phenyl-1,3,4-oxadiazole-2-carbohydrazide (400 mg,1.96 mmol) and acetamidine hydrochloride (573 mg, 6.07 mmol) in xylene(20 mL) NaOH (243 mg, 6.07 mmol) was added. The mixture was stirred at170° C. for 36 h, and then the reaction was cooled to RT, washed withH₂O (20 mL), extracted with 4:1 CHCl₃:i-PrOH (5×50 mL), dried with MgSO₄and concentrated. The crude product was purified on a Biotage pre-packedsilica gel column (MeOH:DCM 2% to 20% MeOH) to afford2-(5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole (100 mg,22%) as a white powder. MS(ES+) C₁₁H₉N₅O requires: 227 found: 228[M+H]⁺.

Step 2

2-(1-((2-Chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole

To a solution of2-(5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole (1.00 mg,0.44 mmol) in DMF (3 mL) Cs₂CO₃ (430 mg, 1.32 mmol), NaI (78 mg, 0.52mmol) and 2-chloro-4-(chloromethyl)pyridine (78 mg, 0.48 mmol) wereadded. The reaction was allowed to stir overnight at RT and then dilutedwith H₂O (10 mL), extracted with EtOAc (3×10 mL), 4:1 CHCl₃:i-PrOH (5×10mL), dried with MgSO₄ and concentrated. The crude product was purifiedon a Biotage pre-packed silica gel column (EtOAc:Hexane 12% to 100%EtOAc) to afford2-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole(88 mg, 57%) as an off-white powder. MS(ES+) C₁₇H₁₃ClN₆O requires: 352found: 353 [M+H]⁺.

What is claimed is:
 1. A compound of structural Formula I(R₁)_(n)-A-Y₁—B-D-E-(R₃)_(p)  (I) or a salt thereof, wherein: n is 0, 1,or 2; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4; u is 0, 1, or 2; A isselected from the group consisting of aryl and heteroaryl; B is selectedfrom the group consisting of

D is selected from the group consisting of alkyl, heteroalkyl, alkoxy,alkylthio, carbonyl, alkylcarbonyl, carboxyl, oxy, thio, sulfinyl,sulfonyl, sulfonamido, amino, amido, alkylamino, and heteroaryl, any ofwhich can be optionally substituted with one or more substituentsselected from the group consisting of hydrogen, deuterium, halogen,alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, and oxo, any of which may be optionallysubstituted; E is selected from the group consisting of aryl andheteroaryl; G is selected from the group consisting of saturated 3- to7-membered cycloalkyl and saturated 3- to 7-membered heterocycloalkyl;R₁ is selected from the group consisting of —Y₂-alkyl-N(R₄)R₅, hydrogen,deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, aminoalkyl, acyl, carboxylalkyl, carbonyl,carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo,alkylthio, thiolalkyl, mercaptyl, thiol, sulfonate, sulfonamido,alkylsulfonyl, amino, amido, alkylamino, dialkylamino, carbamate, nitro,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy,heterocycloalkyloxy, heteroaryloxy,

cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl,heteroarylcarbonyl, cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl,heterocycloalkylcarbonylalkyl, and heteroarylalkyl, any of which can beoptionally substituted with one or more substituents selected from thegroup consisting of hydrogen, deuterium, halogen, alkyl, alkenyl,alkynyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, amidoalkyl,acyl, carbonyl, carboxyl, carboxylalkyl, alkylcarbonyl,heteroalkylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl,alkylaminoalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkoxyalkyl,carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo,alkylthio, thiol, acylthio, sulfonamido, alkylsulfonyl, amino, amido,carbamate, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl,nitro, trisubstituted silyl, trisubstituted siloxy, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, alkylheterocycloalkyl, any of which may beoptionally substituted; R₃ is selected from the group consisting ofhydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acyl, carbonyl,carboxyl, cyano, cyanoalkyl, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,alkoxyalkoxy, hydroxyalkoxy, oxo, alkylthio, mercaptyl, thiol,haloalkylthio, perhaloalkylthio, cyanoalkylthio, haloalkylsulfonyl,alkylsulfonyl, alkoxyalkylsulfonyl, cyanoalkylsulfonyl, sulfonate,sulfonamido, amino, amido, alkylamino, dialkylamino, carbamate, nitro,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy,heterocycloalkyloxy, heteroaryloxy, cycloalkylalkyl, arylalkyl,heterocycloalkylalkyl, and heteroarylalkyl, trisubstituted silyl, —SF₅,—(C(R₃₁)(R₃₂))_(q)—O-alkyl, —(C(R₃₁)(R₃₂))_(q)—O-cycloalkyl,—S(O)_(u)-alkyl, —S(O)_(u)-cycloalkyl, cycloalkylthio, —CF₃, —OCF₃,—(C(R₃₁)(R₃₂))_(q)—OCF₃, saturated heterocycloalkyloxy,—(C(R₃₁)(R₃₂))_(q)—O-saturated heterocycloalkyl,—(C(R₃₁)(R₃₂))_(q)—saturated heterocycloalkyl, saturatedheterocycloalkylthio, —S(O)_(u)-saturated heterocycloalkyl,—(C(R₃₁)(R₃₂))_(q)—OCF₃,

any of which may be optionally substituted; R₄ and R₅ are independentlyselected from the group consisting of hydrogen, deuterium, alkyl,alkenyl, alkynyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl,acyl, carbonyl, carboxyl, alkoxy, haloalkoxy, perhaloalkoxy,alkylsulfonyl, sulfonamido, amido, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, andheteroarylalkyl, or R₄ and R₅, taken together, form a heterocyloalkyl orheteroaryl, any of which can be optionally substituted with one or moresubstituents selected from the group consisting of hydrogen, deuterium,halogen, alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, acyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy,haloalkoxy, perhaloalkoxy, oxo, alkylthio, mercaptyl, thiol, sulfonate,sulfonamido, amino, amido, alkylamino, dialkylamino, carbamate, nitro,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy,heterocycloalkyloxy, heteroaryloxy, cycloalkylalkyl, arylalkyl,heterocycloalkylalkyl, and heteroarylalkyl, any of which may beoptionally substituted; each R₂₃ is independently selected from thegroup consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, acyl, carbonyl,carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo,alkylthio, amino, alkylamino, dialkylamino, nitro, cycloalkyl, aryl, andheteroaryl, any of which may be optionally substituted; R₃₁, R₃₂, R₃₃,R₃₄, and R₃₆ are independently selected from the group consisting ofhydrogen, deuterium, alkyl, and perfluoroalkyl, any of which can beoptionally substituted; R₃₅ is selected from the group consisting ofhydrogen, deuterium, alkyl, perfluoroalkyl, cycloalkyl, and saturatedheterocycloalkyl, any of which can be optionally substituted; R₃₇ andR₃₈ are independently selected from the group consisting of alkyl andperfluoroalkyl, or R₃₇ and R₃₈, taken together, form a heterocyloalkyl,any of which can be optionally substituted; Y₁ is selected from thegroup consisting of alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy,alkylthio, carbonyl, alkylcarbonyl, carboxyl, oxy, thio, sulfinyl,sulfonyl, sulfonamido, amino, amido, alkylamino, and carbamate, any ofwhich can be optionally substituted with one or more substituentsselected from the group consisting of hydrogen, deuterium, halogen,alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, aminoalkyl,acyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, oxo, alkylthio, amino, alkylamino, dialkylamino, andcycloalkyl, any of which may be optionally substituted; Y₂ is selectedfrom the group consisting of a bond, carbonyl, alkylcarbonyl, carboxyl,oxy, thio, sulfinyl, sulfonyl, sulfonamido, amino, amido, alkylamino,and carbamate, any of which can be optionally substituted with one ormore substituents selected from the group consisting of hydrogen,deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl, cyano, hydroxy,alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio, mercaptyl, thiol,sulfonate, sulfonamido, amino, amido, alkylamino, dialkylamino,carbamate, cycloalkyl, aryl, heterocycloalkyl, heteroaryl,cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy,cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, and heteroarylalkyl,any of which may be optionally substituted; if A is phenyl, B is not

wherein Q₂ and Q₃ are freely substituted; if A is phenyl or pyridyl, Y₁is CH₂, B is

and Q₁ is methyl, ethyl, or trifluoromethyl, then D is not

and wherein * represents the point of attachment to Y₁ and ** representsthe point of attachment to D, and # represents the point of attachmentto B and ## represents the point of attachment to E.
 2. The compound asrecited in claim 1 wherein: A is selected from the group consisting ofaryl and mono- or bicyclic heteroaryl; B is selected from the groupconsisting of

D is selected from the group consisting of amido, 5-membered heteroaryl,and 6-membered heteroaryl, any of which can be optionally substitutedwith one or more substituents selected from the group consisting ofhydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, acyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, and oxo,any of which may be optionally substituted; E is selected from the groupconsisting of phenyl, 5-membered heteroaryl, 6-membered heteroaryl, and9-membered bicyclic heteroaryl; R₄ and R₅ are independently selectedfrom the group consisting of hydrogen, deuterium, alkyl, alkenyl,alkynyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl,carbonyl, carboxyl, alkoxy, haloalkoxy, perhaloalkoxy, alkylsulfonyl,sulfonamido, amido, cycloalkyl, aryl, heterocycloalkyl, heteroaryl,cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, and heteroarylalkyl,or R₄ and R₅, taken together, form a heterocyloalkyl or heteroaryl, anyof which can be optionally substituted with one or more substituentsselected from the group consisting of hydrogen, deuterium, halogen,alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl,carbonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,oxo, alkylthio, mercaptyl, thiol, sulfonamido, amino, amido, alkylamino,dialkylamino, carbamate, and cycloalkyl, any of which may be optionallysubstituted; R₂₃ is selected from the group consisting of hydrogen,deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,alkylthio, amino, alkylamino, dialkylamino, cycloalkyl, aryl, andheteroaryl; Y₁ is alkyl, which can be optionally substituted with one ormore substituents selected from the group consisting of hydrogen,deuterium, alkyl, cycloalkyl, and halogen; and Y₂ is selected from thegroup consisting of a bond, carbonyl, alkylcarbonyl, carboxyl, oxy,thio, sulfinyl, sulfonyl, sulfonamido, amino, amido, alkylamino, andcarbamate, any of which can be optionally substituted with one or moresubstituents selected from the group consisting of hydrogen, deuterium,halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl,acyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, oxo, alkylthio, mercaptyl, thiol, sulfonamido, amino,amido, alkylamino, dialkylamino, carbamate, and cycloalkyl, any of whichmay be optionally substituted.
 3. The compound as recited in claim 2wherein: B is


4. The compound as recited in claim 3 wherein: D is selected from thegroup consisting of —C(═O)NR₁₁—, 5-membered heteroaryl, and 6-memberedheteroaryl; E is selected from the group consisting of phenyl,pyrimidine, 1,3-benzodioxol, indole, and 1-benzofuran; R₁ is selectedfrom the group consisting of —Y₂-alkyl-N(R₄)R₅, hydrogen, deuterium,halogen, alkyl, alkenyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, aminoalkyl, acyl, carboxylalkyl, carbonyl, carboxyl,cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio,thiolalkyl, sulfonamido, alkylsulfonyl, amino, amido, alkylamino,dialkylamino, nitro, cycloalkyl, aryl, heterocycloalkyl, heteroaryl,cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy,

cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl, andheterocycloalkylcarbonylalkyl, any of which can be optionallysubstituted with one or more substituents selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl,amidoalkyl, acyl, carboxylalkyl, alkylcarbonyl, heteroalkylcarbonyl,hydroxyalkylcarbonyl, aminoalkylcarbonyl, alkylaminoalkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, alkoxyalkyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, oxo, thiol, acylthio, sulfonamido, alkylsulfonyl, amino,amido, carbamate, alkylamino, dialkylamino, alkylaminoalkyl,dialkylaminoalkyl, trisubstituted silyl, trisubstituted siloxy,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, alkylheterocycloalkyl,any of which may be optionally substituted; R₃ is selected from thegroup consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,dialkylamino, acyl, carbonyl, carboxyl, cyano, cyanoalkyl, hydroxy,alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, hydroxyalkoxy, oxo,alkylthio, haloalkylthio, perhaloalkylthio, cyanoalkylthio,alkylsulfonyl, alkoxyalkylsulfonyl, cyanoalkylsulfonyl,haloalkylsulfonyl, sulfonamido, alkylsulfonamido, amino, alkylamino,dialkylamino, amido, cycloalkyl, aryl, heterocycloalkyl, heteroarylperhaloalkylcycloalkyl, hydroxyheterocycloalkyl, hydroxycycloalkyl,heterocycloalkylcarbonyl, and heterocycloalkylalkyl, any of which can beoptionally substituted; R₁₁ is selected from the group consisting ofhydrogen, deuterium, alkyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, any ofwhich may be optionally substituted; Y₁ is —CH₂—; and Y₂ is selectedfrom the group consisting of a bond, carbonyl, amino, and alkylamino. 5.The compound as recited in claim 4 wherein: A is selected from the groupconsisting of phenyl, 5-membered heteroaryl, and 6-membered heteroaryl;E is phenyl; R₁ is selected from the group consisting of—Y₂-alkyl-N(R₄)R₅, hydrogen, deuterium, halogen, alkyl, alkenyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, carboxylalkyl,carboxyl, carbonyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,oxo, thiolalkyl, sulfonyl, sulfonamido, alkylsulfonyl, amino, amido,alkylamino, dialkylamino, nitro, heterocycloalkyl, heterocycloalkyloxy,

heterocycloalkylcarbonylalkyl, and heterocycloalkylcarbonyl, any ofwhich can be optionally substituted with one or more substituentsselected from the group consisting of hydrogen, deuterium, halogen,alkyl, alkenyl, amidoalkyl, acyl, carboxylalkyl, hydroxyalkylcarbonyl,alkynylcarbonyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, carboxyl,cyano, hydroxy, alkoxy, oxo, sulfonamido, alkylsulfonyl, amino, amido,carbamate, dialkylamino, dialkylaminoalkyl, trisubstituted siloxy,cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, any of which may beoptionally substituted; R₁₁ is selected from the group consisting ofhydrogen, deuterium, alkyl, and cycloalkyl, any of which may beoptionally substituted; and each R₂₃ is independently selected from thegroup consisting of hydrogen, deuterium, hydroxyl, alkyl, haloalkyl,perhaloalkyl, cyano, saturated 3- to 6-membered cycloalkyl, 4- to6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl.
 6. Thecompound as recited in claim 4 wherein: n is 1; p is 1; and R₂₃ isselected from the group consisting of alkyl, haloalkyl, perhaloalkyl,hydroxy, and cyclopropyl.
 7. The compound as recited in claim 2 whereinsaid compound has structural Formula II

or a salt thereof, wherein: X₂, X₄, and X₅ are independently selectedfrom the group consisting of CR₂₁, N, O, and S, and wherein X₂, X₄, andX₅, taken together, form a 5-membered heteroaryl; Z₁ and Z₂ areindependently selected from the group consisting of N, NR₁, C═O, andCR₁; Z₃ is selected from the group consisting of N, NR₁₂, C═O, and CR₁₂;R₁ is selected from the group consisting of —Y₂-alkyl-N(R₄)R₅, hydrogen,deuterium, halogen, alkyl, alkenyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, aminoalkyl, acyl, carboxylalkyl, carbonyl,carboxyl, carbonyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,oxo, alkylthio, thiolalkyl, sulfonyl, sulfonamido, alkylsulfonyl, amino,amido, alkylamino, dialkylamino, nitro, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy,heterocycloalkyloxy, heteroaryloxy,

cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl, andheterocycloalkylcarbonylalkyl, any of which can be optionallysubstituted with one or more substituents selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl,amidoalkyl, acyl, carboxylalkyl, alkylcarbonyl, heteroalkylcarbonyl,hydroxyalkylcarbonyl, aminoalkylcarbonyl, alkylaminoalkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, alkoxyalkyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, oxo, thiol, acylthio, sulfonamido, alkylsulfonyl, amino,amido, carbamate, alkylamino, dialkylamino, alkylaminoalkyl,dialkylaminoalkyl, trisubstituted silyl, trisubstituted siloxy,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, alkylheterocycloalkyl,any of which may be optionally substituted; R₁₂, R₁₃, and R₁₄ areindependently selected from the group consisting of hydrogen, deuterium,halogen, alkyl, haloalkyl, perhaloalkyl, cyano, hydroxy, alkoxy,haloalkoxy, perhaloalkoxy, alkylthio, amino, and saturated 3- to7-membered cycloalkyl, any of which may be optionally substituted; R₁₆,R₁₉, and R₂₀ are independently selected from the group consisting ofhydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, amino, andcycloalkyl, any of which may be optionally substituted; R₁₇ and R₁₈ areindependently selected from the group consisting of hydrogen, deuterium,halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, dialkylamino, acyl, carbonyl, carboxyl, cyano,cyanoalkyl, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy,hydroxyalkoxy, oxo, alkylthio, haloalkylthio, perhaloalkylthio,cyanoalkylthio, alkylsulfonyl, alkoxyalkylsulfonyl, cyanoalkylsulfonyl,haloalkylsulfonyl, sulfonamido, alkylsulfonamido, amino, alkylamino,dialkylamino, amido, cycloalkyl, aryl, heterocycloalkyl, heteroarylperhaloalkylcycloalkyl, hydroxyheterocycloalkyl, hydroxycycloalkyl,heterocycloalkylcarbonyl, and heterocycloalkylalkyl, any of which can beoptionally substituted; R₂₁ is selected from the group consisting ofnull, hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, alkylthio, amino, alkylamino, and dialkylamino; and R₂₃is selected from the group consisting of hydrogen, deuterium, hydroxyl,alkyl, haloalkyl, perhaloalkyl, cyano, saturated 3- to 6-memberedcycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-memberedheteroaryl.
 8. The compound as recited in claim 7 wherein: two of X₂,X₄, and X₅ are N; and one of X₂, X₄, and X₅ is O; or one of X₂, X₄, andX₅ is N; one of X₂, X₄, and X₅ is O; and one of X₂, X₄, and X₅ is CH;and R₂₃ is selected from the group consisting of hydrogen, deuterium,hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, and saturated 3- to6-membered cycloalkyl.
 9. The compound as recited in claim 7 wherein: atleast one of Z₁ or Z₂ is CR₁; R₁ is selected from the group consistingof —Y₂-alkyl-N(R₄)R₅, hydrogen, deuterium, halogen, alkyl, alkenyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, carboxylalkyl,carboxyl, carbonyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,oxo, thiolalkyl, sulfonyl, sulfonamido, alkylsulfonyl, amino, amido,alkylamino, dialkylamino, nitro, heterocycloalkyl, heterocycloalkyloxy,

heterocycloalkylcarbonylalkyl, and heterocycloalkylcarbonyl, any ofwhich can be optionally substituted with one or more substituentsselected from the group consisting of hydrogen, deuterium, halogen,alkyl, alkenyl, amidoalkyl, acyl, carboxylalkyl, hydroxyalkylcarbonyl,alkynylcarbonyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, carboxyl,cyano, hydroxy, alkoxy, oxo, sulfonamido, alkylsulfonyl, amino, amido,carbamate, dialkylamino, dialkylaminoalkyl, trisubstituted siloxy,cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, any of which may beoptionally substituted; R₁₂, R₁₃, and R₁₄ are hydrogen; R₁₆, R₁₇, R₁₉,and R₂₀ are hydrogen; R₂₁ is selected from the group consisting of null,hydrogen, deuterium, halogen, and alkyl; and R₂₃ is selected from thegroup consisting of hydrogen, deuterium, hydroxyl, alkyl, haloalkyl,perhaloalkyl, cyano, and saturated 3- to 6-membered cycloalkyl.
 10. Thecompound as recited in claim 9 wherein: R₁ is selected from the groupconsisting of hydrogen, deuterium, fluorine, bromine, cyano, methyl,isopropyl,

ethylene,

trifluoromethyl, bromomethyl, hydroxymethyl, difluoromethoxy, methoxy,ethoxy, isopropoxy, hydroxy, nitro, acetyl, carboxyl, —CO₂CH₃,

—SO₂CH₃, —SO₂CH₂CH₃, SO₂CH₂CH₂CH₃, —SO₂NH₂,

amino, methylamino, dimethylamino,

R₁₈ is selected from the group consisting of hydrogen, deuterium,halogen, methyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, acetyl,hydroxymethyl, methoxymethyl, methoxy, isopropoxy, methylamino,dimethylamino, methylthio, cyanomethyl, cyanomethylthio, cyano, —SO₂CH₃,—SO₂CH(CH₃)₂, —SO₂CH₂CH(CH₃)₂, —SO₂NHCH₂CH₂CH₃, —SO₂CHF₂, —SO₂CF₃,

trifluoromethyl, trifluoromethylthio, difluoromethoxy, andtrifluoromethoxy; R₂₂ is selected from the group consisting of hydrogen,deuterium, methyl, acetyl,

and R₂₃ is selected from the group consisting of hydrogen, deuterium,methyl, ethyl, 3-pyridyl, and cyclopropyl.
 11. The compound as recitedin claim 10 wherein: R₁ is selected from the group consisting ofhydrogen, halogen, cyano, methyl, isopropyl,

ethylene, trifluoromethyl, difluoromethoxy, methoxy, ethoxy, isopropoxy,hydroxy, carboxyl, —CO₂CH₃, —SO₂CH₃, —SO₂NH₂,

amino, methylamino, dimethylamino,

and R₂₃ is methyl.
 12. The compound as recited in claim 11 wherein twoof X₂, X₄, and X₅ are N; and one of X₂, X₄, and X₅ is O.
 13. Thecompound as recited in claim 11 wherein one of X₂, X₄, and X₅ is N; oneof X₂, X₄, and X₅ is O; and one of X₂, X₄, and X₅ is CH.
 14. Thecompound as recited in claim 9, wherein said compound has structuralFormula III:

or a salt thereof, wherein: X₂ and X₄ are N and X₅ is O; X₄ and X₅ are Nand X₂ is O; X₂ and X₅ are N and X₄ is O; X₂ is CH, X₄ is N, and X₅ isO; or X₂ is CH, X₄ is O, and X₅ is N; Z₂ is selected from the groupconsisting of N and CR₁₄; R₁ is selected from the group consisting ofheterocycloalkyl, alkoxyalkoxy, alkylsulfonylalkoxy,heterocycloalkyloxy, heterocycloalkylcarbonyl, alkoxyalkylamido,heterocycloalkylsulfonyl, alkoxyalkylsulfonamido, wherein saidheterocycloalkyl, heterocycloalkyloxy, heterocycloalkylcarbonyl, andheterocycloalkylsulfonyl can be optionally substituted with one or moresubstituents selected from the group consisting hydrogen, alkyl, andoxo; R₁₄, R₃₉, and R₄₀ are independently selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,alkylthio, amino, and saturated 3- to 7-membered cycloalkyl, any ofwhich may be optionally substituted; and R₁₈ is selected from the groupconsisting of alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy,perhaloalkoxy, alkylthio, haloalkylthio, and perhaloalkylthio.
 15. Thecompound as recited in claim 14 wherein R₁ is selected from the groupconsisting of


16. The compound as recited in claim 14 wherein R₁₈ is selected from thegroup consisting of isopropyl, tert-butyl, —CF₃, —OCF₃, —OCHF₂, and—SCF₃.
 17. The compound as recited in claim 14 wherein: R₁ is selectedfrom the group consisting of

R₁₃, R₁₄, R₁₆, R₁₇, and R₁₉ are hydrogen; and R₁₈ is selected from thegroup consisting of isopropyl, tert-butyl, —CF₃, —OCF₃, —OCHF₂, and—SCF₃.
 18. The compound as recited in claim 2 wherein said compound hasstructural Formula IV

or a salt thereof, wherein: Z₁ and Z₂ are independently selected fromthe group consisting of N, NR₁, C═O, and CR₁; Z₃ is selected from thegroup consisting of N, NR₁₂, C═O, and CR₁₂; R₁ is selected from thegroup consisting of —Y₂-alkyl-N(R₄)R₅, hydrogen, deuterium, halogen,alkyl, alkenyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl,aminoalkyl, acyl, carboxylalkyl, carbonyl, carboxyl, carbonyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio, thiolalkyl,sulfonyl, sulfonamido, alkylsulfonyl, amino, amido, alkylamino,dialkylamino, nitro, cycloalkyl, aryl, heterocycloalkyl, heteroaryl,cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy,

cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl, andheterocycloalkylcarbonylalkyl, any of which can be optionallysubstituted with one or more substituents selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl,amidoalkyl, acyl, carboxylalkyl, alkylcarbonyl, heteroalkylcarbonyl,hydroxyalkylcarbonyl, aminoalkylcarbonyl, alkylaminoalkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, alkoxyalkyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, oxo, thiol, acylthio, sulfonamido, alkylsulfonyl, amino,amido, carbamate, alkylamino, dialkylamino, alkylaminoalkyl,dialkylaminoalkyl, trisubstituted silyl, trisubstituted siloxy,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, alkylheterocycloalkyl,any of which may be optionally substituted; R₁₁ is selected from thegroup consisting of hydrogen, deuterium, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl; R₁₂, R₁₃, and R₁₄ are independently selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,alkylthio, amino, and saturated 3- to 7-membered cycloalkyl, any ofwhich may be optionally substituted; R₁₆, R₁₉, and R₂₀ are independentlyselected from the group consisting of hydrogen, deuterium, halogen,alkyl, haloalkyl, perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, alkylthio, amino, and cycloalkyl, any of which may beoptionally substituted; R₁₇ and R₁₈ are independently selected from thegroup consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,dialkylamino, acyl, carbonyl, carboxyl, cyano, cyanoalkyl, hydroxy,alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, hydroxyalkoxy, oxo,alkylthio, haloalkylthio, perhaloalkylthio, cyanoalkylthio,alkylsulfonyl, alkoxyalkylsulfonyl, cyanoalkylsulfonyl,haloalkylsulfonyl, sulfonamido, alkylsulfonamido, amino, alkylamino,dialkylamino, amido, cycloalkyl, aryl, heterocycloalkyl, heteroarylperhaloalkylcycloalkyl, hydroxyheterocycloalkyl, hydroxycycloalkyl,heterocycloalkylcarbonyl, and heterocycloalkylalkyl, any of which can beoptionally substituted; and R₂₃ is selected from the group consisting ofhydrogen, deuterium, hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano,saturated 3- to 6-membered cycloalkyl, 4- to 6-memberedheterocycloalkyl, and 5- to 6-membered heteroaryl.
 19. A compoundselected from the group consisting of Examples 1 to 163, or a saltthereof.
 20. A pharmaceutical composition comprising a compound asrecited in claim 1 together with a pharmaceutically acceptable carrier.21. A method of treatment of a HIF pathway-mediated disease comprisingthe administration of a therapeutically effective amount of a compoundas recited in claim 1 to a patient in need thereof.
 22. The method asrecited in claim 21 wherein said disease is cancer.
 23. The method asrecited in claim 22 wherein said cancer is selected from the groupconsisting of colon cancer, breast cancer, ovarian cancer, lung cancer,prostrate cancer; cancers of the oral cavity and pharynx (lip, tongue,mouth, larynx, pharynx), esophagus, stomach, small intestine, largeintestine, colon, rectum, liver and biliary passages; pancreas, bone,connective tissue, skin, cervix, uterus, corpus endometrium, testis,bladder, kidney and other urinary tissues, including renal cellcarcinoma (RCC); cancers of the eye, brain, spinal cord, and othercomponents of the central and peripheral nervous systems, as well asassociated structures such as the meninges; cancers of the thyroid andother endocrine glands; Hodgkin's disease, non-Hodgkin's lymphomas,multiple myeloma, hematopoietic malignancies including leukemias(Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL))and lymphomas including lymphocytic, granulocytic and monocytic;adrenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplasticastrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma,choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma,cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma,Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer,genitourinary tract cancers, glioblastoma multiforme, head and neckcancer, hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi'ssarcoma, large cell carcinoma, leiomyosarcoma, leukemias, liposarcoma,lymphatic system cancer, lymphomas, lymphangiosarcoma,lymphangioendotheliosarcoma, medullary thyroid carcinoma,medulloblastoma, meningioma mesothelioma, myelomas, myxosarcomaneuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma,epithelial ovarian cancer, papillary carcinoma, papillaryadenocarcinomas, paraganglioma, parathyroid tumours, pheochromocytoma,pinealoma, plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceousgland carcinoma, seminoma, skin cancers, melanoma, small cell lungcarcinoma, non-small cell lung carcinoma, squamous cell carcinoma, sweatgland carcinoma, synovioma, thyroid cancer, uveal melanoma, and Wilm'stumor.
 24. A method of treatment of a disease caused by abnormal cellproliferation comprising the administration of a therapeuticallyeffective amount of a compound as recited in claim 1 to a patient inneed thereof.
 25. A method of treatment of a HIF pathway-mediateddisease comprising the administration of: a. a therapeutically effectiveamount of a compound as recited in claim 1; and b. another therapeuticagent.
 26. A method for achieving an effect in a patient comprising theadministration of a therapeutically effective amount of a compound asrecited in claim 1 to a patient, wherein the effect is selected from thegroup consisting of preventing or reducing resistance to radiotherapyand chemotherapy, preventing or reducing tumor invasion and tumormetastasis, and preventing or reducing angiogenesis.